Medicinal Plant-derived Phytochemicals as Adjunct Modulators of PI3K–AKT–mTOR Signaling in Breast Cancer: A Mini Review

Abstract

The phosphatidylinositol 3-kinase (PI3K)–Protein kinase B (AKT)–mechanistic target of rapamycin (mTOR) signaling axis represents one of the most important oncogenic pathways in breast cancer and a major driver of therapeutic resistance, particularly in hormone receptor–positive, and triple-negative subtypes. Although PI3K and mTOR inhibitors such as alpelisib and everolimus have improved clinical outcomes in selected patients, their broader application is limited by toxicity and adaptive resistance mechanisms. Increasing attention has therefore been directed toward medicinal plant-derived phytochemicals as multi-target modulators of this pathway. This review summarizes current mechanistic evidence showing how selected phytochemicals—including flavonoids, polyphenols, and isothiocyanates—interfere with PI3K–AKT–mTOR signaling at multiple nodes, suppress compensatory survival pathways, and enhance the efficacy of endocrine therapy, chemotherapy, and targeted agents. Rather than acting as standalone therapies, these compounds are increasingly viewed as adjunctive modulators or lead scaffolds for anticancer drug development. This mini review uniquely integrates emerging evidence on phytochemical modulation of the PI3K–AKT–mTOR axis with mechanisms of therapeutic resistance and rational combination strategies with targeted therapies. It also highlights recent advances in nanoformulation technologies that may improve phytochemical bioavailability and facilitate clinical translation in precision breast cancer therapy.

Introduction

Breast cancer is one of the major causes of cancer morbidity and mortality across the globe despite the development of screening and systemic therapies. Its management is complicated by its high molecular heterogeneity that divides tumors into biologically distinct subtypes such as hormone receptor–positive, triple-negative, and human epidermal growth factor receptor 2-positive breast cancers. Each of those has a different prognosis and treatment response.^1,2 This heterogeneity is a crucial factor in the variation in treatment efficacy and thus increases the need for molecularly focused therapeutic methods.

The phosphatidylinositol 3-kinase (PI3K)–Protein kinase B (AKT)–mechanistic target of rapamycin (mTOR) axis is one of the key oncogenic signaling pathways implicated in breast cancer pathogenesis. ³ Abnormal activation of this pathway promotes cellular proliferation, survival, angiogenesis, metabolic reprogramming, and metastatic progression. ⁴ Persistent activation of the PI3K–AKT–mTOR pathway in breast cancer is frequently driven by genomic alterations, including activating Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, loss of Phosphatase and tensin homolog (PTEN), and aberrant upstream receptor tyrosine kinase signaling. ⁵ Notably, hyperactivation of PI3K and mTOR signaling has been closely associated with resistance to endocrine therapy, chemotherapy, and targeted therapies in hormone receptor–positive and triple-negative breast cancer subtypes.^6,7

The clinical importance of this pathway is underscored by the regulatory approval of PI3K and mTOR inhibitors, including alpelisib and everolimus, for selected groups of breast cancer patients.^8,9 These agents have been shown to improve progression-free survival when combined with conventional therapies. However, their wider clinical applicability remains limited. Adverse effects such as hyperglycemia, mucositis, dermatologic toxicity, and immunosuppression represent dose-limiting toxicities that may compromise treatment adherence. ¹⁰ Furthermore, adaptive feedback activation of compensatory signaling pathways and intratumoral heterogeneity contribute to the development of acquired resistance, thereby reducing long-term therapeutic effectiveness. ¹¹

Methods

A literature search was conducted using electronic databases including PubMed, Scopus, Web of Science, and Chocrane up to January 2026. Boolean operators were used to refine and broaden the search where appropriate. Representative search strings included: (“breast cancer” OR “mammary carcinoma”) AND (“PI3K–AKT–mTOR”) AND (“phytochemical” OR “natural compound” OR “plant-derived compound”) AND (“curcumin” OR “resveratrol” OR “quercetin” OR “genistein” OR “epigallocatechin-3-gallate” OR “EGCG” OR “sulforaphane” OR “berberine”). Additional relevant publications were identified through manual screening of reference lists from key review articles and primary research papers to ensure comprehensive coverage of the topic.

Articles were included if they investigated plant-derived phytochemicals or natural compounds with reported modulatory effects on the PI3K–AKT–mTOR signaling pathway in breast cancer. Both experimental and mechanistic studies were considered, including in vitro, in vivo, and translational research, provided that they examined molecular interactions or signaling mechanisms involving PI3K, AKT, mTOR, or related upstream regulators. Studies focusing exclusively on non-plant synthetic compounds, unrelated cancer types, or lacking mechanistic relevance to PI3K–AKT–mTOR signaling were excluded. Relevant data from eligible studies were extracted and synthesized qualitatively to identify common mechanistic themes across different phytochemicals. Extracted variables included primary pathway node, phytochemical, chemical class/source, key mechanistic actions on PI3K–AKT–mTOR signaling, and relevance to therapy resistance, which were used to organize the evidence.

In light of these limitations, there is growing interest in complementary approaches that may enable more tolerable and sustained modulation of the PI3K–AKT–mTOR pathway. Medicinal plant-derived phytochemicals have emerged as promising candidates because of their structural diversity, multi-target activity, and generally favorable safety profiles. ¹² A growing body of preclinical data suggests that multiple phytochemicals may interfere directly or indirectly with key mediators of the PI3K–AKT–mTOR signaling pathway, resulting in impaired tumor cell proliferation, promotion of apoptosis or autophagy, and increased sensitivity to traditional anticancer agents. ¹³ Rather than being used as standalone therapies, these compounds are increasingly being explored as adjunctive modulators or lead scaffolds for drug development. Based on these observations, this mini review synthesizes current mechanistic and translational evidence on medicinal plant-derived phytochemicals that modulate the PI3K–AKT–mTOR signaling pathway in breast cancer. This review focuses on how these compounds may be incorporated into combination strategies and used to address therapeutic resistance. A growing body of mechanistic evidence suggests that medicinal plant-derived phytochemicals can regulate multiple nodes of the PI3K–AKT–mTOR signaling pathway, which plays a central role in breast cancer progression and treatment resistance.

Despite increasing evidence describing natural compounds with anticancer properties, relatively few reviews have specifically examined medicinal plant-derived phytochemicals as modulators of the PI3K–AKT–mTOR signaling axis in the context of therapeutic resistance in breast cancer. Most previous studies have focused primarily on general anticancer activities of phytochemicals without systematically linking their molecular effects to clinically relevant resistance mechanisms associated with PI3K pathway activation. Considering that dysregulation of PI3K–AKT–mTOR signaling is strongly implicated in endocrine resistance, chemotherapy resistance, and targeted therapy resistance in breast cancer,^6,7,20 a focused synthesis of phytochemical-based modulation of this pathway is warranted. Therefore, this mini review summarizes current mechanistic evidence describing how selected medicinal plant-derived phytochemicals regulate different nodes of the PI3K–AKT–mTOR signaling network and influence resistance-related signaling pathways. In addition, this review highlights emerging translational perspectives, including rational combination strategies with endocrine therapy, PI3K inhibitors, mTOR inhibitors, and Cyclin-dependent kinase (CDK4)/ 6 inhibitors, as well as advances in nanoformulation technologies designed to improve phytochemical bioavailability and therapeutic delivery. By integrating mechanistic insights with translational considerations, this review aims to provide a clearer framework for the potential development of phytochemical-based adjunct strategies in precision breast cancer therapy.

Results

PI3K–AKT–mTOR Signaling in Breast Cancer: Mechanistic Overview

In breast cancer, the PI3K–AKT–mTOR signaling pathway is a central regulator of cellular growth, survival, metabolism, and therapeutic response. This pathway is activated through upstream receptor tyrosine kinases or G protein–coupled receptors. In addition, one of the most common molecular alterations in breast cancer involves activating mutations of the p110α catalytic subunit encoded by the PIK3CA gene, which occur in approximately 30%–40% of hormone receptor–positive tumors. ¹⁴ These mutations lead to sustained production of phosphatidylinositol-3,4,5-trisphosphate, resulting in persistent activation of downstream signaling pathways. ⁵ Even in the absence of external growth factors, these alterations can sustain downstream signaling. ¹⁵

AKT activation is regulated through sequential phosphorylation events in which phosphoinositide-dependent kinase-1 phosphorylates AKT at Thr308, while mTOR complex 2 (mTORC2) phosphorylates AKT at Ser473, together enabling full kinase activation. Once activated, AKT phosphorylates downstream targets such as glycogen synthase kinase-3β, β-catenin, forkhead box O transcription factors, and tuberous sclerosis complex proteins, thereby promoting multiple oncogenic processes, including anti-apoptotic signaling, cell survival, and metabolic reprogramming. ¹⁶ The persistence of AKT signaling is a reliable indication of tumor aggressiveness and treatment resistance in breast cancer. ¹⁷

Mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism that exists in two multiprotein complexes (mTOR complex 1 [mTORC1] and mTORC2), each with distinct biological functions. mTORC1 integrates signals from growth factors, nutrients, and cellular energy status to affect protein synthesis, lipid biosynthesis, and autophagy (ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1). mTORC2, on the other hand, regulates cytoskeleton organization and cell survival and functions as an upstream activator of AKT. ¹⁸ Both complexes are implicated in tumor progression, although current clinical inhibitors predominantly target mTORC1. Current pharmacological inhibitors primarily target mTORC1, which results in incomplete pathway suppression and compensatory feedback activation. ¹⁸

The PI3K–AKT–mTOR signaling pathway has multiple biological and clinical implications in different subtypes of breast cancer. Hyperactivation of the signal transduction pathway is closely associated with endocrine therapy resistance in estrogen receptor (ER)-positive diseases, which is caused by bidirectional crosstalk between the ER and PI3K signaling networks. ¹⁹ The reliance on PI3K–AKT–mTOR signaling has been implicated closely with metabolic adjustment, increased glycolysis, and survival in the hypoxic and nutrient-starved condition in triple-negative breast cancer, which does not possess any established molecular target. ²⁰ These subtype-specific functions highlight the importance of targeting pathways in a variety of clinical settings.

PI3K–AKT–mTOR Signaling and Therapeutic Resistance in Breast Cancer

Dysregulation of the PI3K–AKT–mTOR signaling axis represents one of the most important molecular mechanisms underlying therapeutic resistance in breast cancer. Activation of this pathway promotes tumor cell survival, metabolic adaptation, and inhibition of apoptosis, thereby enabling cancer cells to escape the cytotoxic effects of systemic therapies. In hormone receptor–positive breast cancer, bidirectional crosstalk between ER signaling and the PI3K pathway contributes significantly to endocrine resistance by allowing tumor cells to maintain proliferative signaling despite estrogen deprivation. ¹⁹ Similarly, activation of PI3K–AKT–mTOR signaling has been implicated in resistance to CDK4/6 inhibitors through compensatory cell cycle activation and enhanced cyclin D1 expression. ⁶ In triple-negative breast cancer, where targeted therapeutic options are limited, persistent activation of the PI3K pathway supports metabolic plasticity, tumor cell survival under stress conditions, and resistance to chemotherapy. ²⁰ In addition, inhibition of mTORC1 alone may paradoxically trigger feedback activation of upstream receptor tyrosine kinases and AKT signaling, further contributing to adaptive resistance mechanisms.^11,58 These observations highlight the complexity of targeting this pathway using single-agent inhibitors and emphasize the need for multi-target therapeutic strategies capable of suppressing compensatory survival networks. Emerging evidence suggests that medicinal plant-derived phytochemicals may modulate several nodes of the PI3K– AKT–mTOR signaling cascade simultaneously, thereby providing a potential adjunctive approach to overcome resistance and enhance the efficacy of existing anticancer therapies. These resistance mechanisms provide a strong rationale for investigating multi-target natural compounds capable of simultaneously modulating several components of the PI3K–AKT–mTOR pathway.

The hierarchical organization of the PI3K– AKT–mTOR signaling pathway and its feedback activation loops that contribute to therapeutic resistance in breast cancer are illustrated in Figure 1. This conceptual framework highlights key molecular nodes where phytochemical compounds may exert modulatory effects, thereby providing a mechanistic rationale for their potential use as adjunctive therapeutic agents.

Figure 1.

PI3K–AKT–mTOR Signaling Hierarchy and Feedback Activation Underlying Therapeutic Resistance in Breast Cancer. Figure Created by the Authors using BioRender (BioRender.com, Version 2025).

Medicinal Plant-derived Phytochemicals Modulating PI3K–AKT–mTOR Signaling

Modulation of PI3K Activation

Several phytochemicals suppress pathway signaling at the level of PI3K. The mechanism works through direct inhibition of catalytic activity or by attenuating upstream drivers that converge on PI3K activation. One of the investigated phytochemicals that inhibits PI3K signaling is quercetin, which is a flavonol abundant in fruits and vegetables. Quercetin directly inhibits PI3K catalytic activity by binding to the Adenosine triphosphate (ATP)-binding pocket of the p110 subunit, resulting in reduced downstream phosphorylation of AKT. In breast cancer cell lines, quercetin inhibits proliferation, induces apoptosis, and suppresses migration through inhibition of PI3K–AKT signaling. ²¹ Notably, quercetin is more active in ER-positive breast cancer models by inhibiting the ER-dependent activation of PI3K signaling. This mechanism may increase tumor cell sensitivity to endocrine therapy. ²² Evidence from in vivo tumor-bearing mouse models has demonstrated that combinations of phytochemicals including resveratrol, curcumin, and quercetin, can suppress tumor growth and modulate tumor-associated immune responses. ²³

Genistein, a soy-derived isoflavone, has attracted interest because of its dual role as a phytoestrogen and modulator of the PI3K pathway. Genistein inhibits PI3K signaling at the molecular level by lowering PIK3CA expression and preventing AKT activation by PI3K. ²⁴ Genistein also interferes with receptor tyrosine kinase signaling upstream of PI3K, which further inhibits pathway activation in breast cancer cells. ²⁵ It also disrupts ER–PI3K crosstalk in ER-positive breast cancer models, thereby suppressing tumor growth and reducing endocrine resistance. ²⁶ Preclinical in vivo experiments have confirmed that genistein inhibits tumor growth and enhances the action of conventional treatments. However, due to its estrogenic properties, its dosage and disease environment must be carefully considered. ²⁷

Berberine, which is a plant-derived isoquinoline alkaloid, has emerged as a potent PI3K signaling inhibitor with extensive anticancer activity. It inhibits the PI3K–AKT signaling pathway by downregulating PIK3CA expression and suppressing PI3K enzymatic activity, resulting in reduced AKT phosphorylation and downstream PI3K–AKT–mTOR Signaling. ²⁸ Berberine can induce cell cycle arrest and apoptosis as well as prevent epithelial–mesenchymal transition, which are closely associated with the activation of PI3K in breast cancer models. ²⁹ Berberine has shown activity across several breast cancer subtypes, including triple-negative breast cancer. In this case, PI3K signaling acts to promote metabolic adjustment and survival. ³⁰ Its antitumor effects and safety profile are effective in animal studies, advancing its use as an adjunctive agent. ³¹ Notably, many mechanistic studies evaluating phytochemicals such as quercetin, curcumin, and resveratrol employ concentrations that exceed achievable plasma levels in humans, raising concerns regarding physiological relevance and translational applicability and highlighting the need for careful interpretation of preclinical findings.^59,67

Regulation of AKT Phosphorylation and Downstream Survival Signaling

AKT is a central downstream effector of the PI3K signaling pathway that integrates growth factor, metabolic, and survival signals in breast cancer. Persistent AKT signaling may promote tumor progression, resistance to apoptosis, and reduced sensitivity to multiple therapeutic agents. ³² Therefore, phytochemicals capable of regulating AKT phosphorylation and downstream signal transduction have attracted considerable interest as complementary therapeutic agents.

Curcumin, which is a polyphenol found in turmeric (Curcuma longa), is currently being studied as one of the phytochemicals involved in AKT signaling that has significant potential. Several studies have shown that curcumin inhibits AKT activation by suppressing phosphorylation at Thr308 and Ser473, leading to downstream inhibition of PI3K–AKT–mTOR signaling. ³³ Curcumin induces apoptosis in breast cancer cell lines through activation of caspase-dependent pathways and causes cell cycle arrest at the G1 or G2/M phase. The dominant mechanism may vary according to the molecular subtype. ³⁴ By inhibiting AKT-dependent survival signaling and interfering with feedback loops, curcumin has been reported to reverse endocrine and chemotherapy resistance. ³⁵ However, this substance has not been fully translated to clinical use due to its low bioavailability, despite the development of novel formulations.

Resveratrol is a natural polyphenol found in grapes and berries that exhibits anticancer activity. Its function is to reverse a variety of signaling pathways, including AKT. Resveratrol inhibits cell proliferation and promotes apoptosis by decreasing AKT phosphorylation and interfering with AKT-stimulated subsequent signals. ³⁶ In addition, resveratrol induces cell cycle arrest by regulating cyclin-dependent kinases and stimulating mitochondrial-mediated apoptosis in breast cancer models. ³⁷ It is also worth noting that resveratrol has been shown to sensitize breast cancer cells to chemotherapeutic agents and endocrine therapy by inhibiting AKT-driven resistance mechanisms. ³⁸ Such effects appear to be of particular significance in hormone receptor–positive diseases, particularly when AKT signaling is involved in estrogen-independent development.

Luteolin is a flavonoid found in many medicinal plants and foods that is an effective AKT signaling inhibitor. Luteolin inhibits AKT phosphorylation and subsequent mTOR activation. This effect reduces cell proliferation and increases apoptotic signaling in breast cancer cells. ³⁹ In addition to inducing apoptosis, luteolin promotes cell cycle arrest through modulation of cyclin D1 and p21 expression. ⁴⁰ Recent evidence suggests that luteolin can suppress epithelial–mesenchymal transition and metastatic potential by inhibiting AKT-dependent processes, thereby improving therapeutic responsiveness. ⁴¹ The effects of these substances have been observed in several subtypes of breast cancer, including triple-negative breast cancer.

Curcumin, resveratrol, and luteolin combinations have been shown to regulate AKT activation through synergistic actions that cause apoptosis, cell cycle blockage, and inhibition of resistance signaling.^42–44 Given the central role of AKT as a mediator of therapeutic resistance, these phytochemicals may have potential as adjunctive agents to improve the efficacy of breast cancer treatment. ⁴⁵ Combining the three could have a multi-target effect, which may provide an advantage over single-target synthetic inhibitors by reducing compensatory pathway activation. ⁴⁶

Targeting mTOR Complexes and Metabolic Signaling

mTOR functions as a key regulator of cellular metabolism, protein synthesis, and autophagy. It is formed as two complexes, namely mTORC1 and mTORC2. ¹⁸ PI3K–AKT–mTOR signaling is dysregulated in ways that promote malignant growth, metabolic adaptation, and therapeutic resistance, as evidenced by ongoing mTORC1-regulated translation and feedback induction of upper PI3K–AKT signaling in breast cancer cases. ⁴⁷ Although synthetic mTOR inhibitors have already proven useful in clinical practice, their drawbacks have led to the consideration of medicinal plant-derived compounds with the ability to regulate PI3K–AKT–mTOR signaling with multi-target effects. ⁴⁸

Epigallocatechin-3-gallate (EGCG) is one of the main catechins in green tea (Camellia sinensis). Studies have shown that EGCG can inhibit PI3K–AKT–mTOR signaling in breast cancer models. Scientifically, EGCG is reported to inhibit mTORC1, which causes phosphorylation of downstream targets such as S6 kinase and 4E-binding protein 1, thereby inhibiting protein synthesis and proliferation. ⁴⁹ EGCG also causes metabolic stress by modulating the AMP-activated protein kinase (AMPK), which inhibits mTORC1, and promotes autophagy. ⁵⁰ In addition, EGCG has also been shown to reduce viability and inhibit invasive behavior in ER-positive and triple-negative breast cancer cell lines, and it is more effective when combined with other anticancer agents. ⁵¹ These findings support the potential use of EGCG as a promising adjunctive compound against mTOR-dependent tumor growth.

Sulforaphane is an isothiocyanate found in cruciferous vegetables such as broccoli (Brassica oleracea). In addition, the substance has been extensively studied for its anticancer capabilities and also its ability to inhibit mTOR signaling. The role of sulforaphane is to activate AMPK and block AKT-mediated signaling and induce autophagy, as well as inhibit mTORC1.^52,53 Sulforaphane has been found to be effective in breast cancer models by targeting cancer stem-like populations. Based on the current study, the substance has been linked to inhibiting tumor initiation and progression in preclinical models. ⁵⁴ These effects may be particularly relevant in triple-negative breast cancer, in which mTOR-related metabolic dependence and therapeutic resistance contribute to clinical aggressiveness. ⁵⁵

Honokiol is a biphenolic lignan derived from Magnolia species that exhibits anti-proliferative and pro-apoptotic effects in breast cancer. It has been shown to inhibit mTOR signaling by inhibiting PI3K–AKT and mTOR downstream phosphorylation. ⁵⁶ Honokiol can also induce autophagy that may involve metabolic stress signaling pathways that lead to mTORC1 inhibition. ⁵⁷ Notably, honokiol has shown efficacy in breast cancer models that are thought to be therapy resistant, implying that it will be useful in overcoming mTOR-stimulated survival signaling.

A summary of representative medicinal plant-derived phytochemicals that target key nodes of the PI3K–AKT–mTOR signaling pathway and their potential relevance to therapeutic resistance in breast cancer is presented in Table 1.

Table 1.

Representative Medicinal Plant-derived Phytochemicals Targeting Key Nodes of the PI3K–AKT–mTOR Signaling Pathway and Their Potential Relevance to Therapeutic Resistance in Breast Cancer.

Category (Primary Pathway Node)	Phytochemical	Chemical Class/Source	Key Mechanistic Actions on PI3K–AKT–mTOR Signaling	Relevance to Therapy Resistance/Translation	References
PI3K pathway modulators	Quercetin	Flavonol/fruits and vegetables	PI3K catalytic activity is inhibited by direct interaction with the p110 ATP-binding pocket and resulting in decreased AKT phosphorylation and downstream signaling.	Improves endocrine sensitization of ER-positive breast cancer/inhibits proliferation and migration at a good safety in preclinical models.	21–23
	Genistein	Isoflavone/soy products	Disables the PIK3CA gene and inhibits AKT upstream RTK signaling; suppresses upstream RTK signaling.	Crosstalk with ER-PI3K disrupts, and endocrine resistance/estrogenic properties require careful dosing considerations	24–26
	Berberine	Isoquinoline alkaloid/ medicinal plants	Reduces PI3K activity and PIK3CA transcription, which inhibits AKT phosphorylation and downstream mTOR signaling.	Active in breast cancer subtypes such as TNBC/inhibits EMT and metabolic plasticity linked to resistance.	28–31
AKT phosphorylation regulators	Curcumin	Polyphenol/Curcuma longa	Prevents AKT Thr308 and Ser473 phosphorylation, which inhibits downstream survival signaling pathways and mTOR.	Reverses endocrine and chemotherapy resistance/translation is limited by low bioavailability.	33–35
	Resveratrol	Polyphenol/grapes and berries	Inhibits AKT phosphorylation and downstream pathways, resulting in apoptosis and cell cycle arrest.	Breast cancer cells are sensitized to endocrine and chemotherapeutic agents, especially in hormone receptor–positive diseases.	36–38
	Luteolin	Flavonoid/ medicinal plants and foods	Blocks AKT phosphorylation and subsequent mTOR stimulation; inhibits EMT and metastatic signaling.	Improves therapeutic responsiveness across subtypes, including TNBC.	39–41
	Curcumin + Resveratrol + Luteolin	Polyphenol/flavonoid combination	The combination of inhibiting AKT activation, increasing apoptosis, and suppressing resistance signaling.	Potential adjunct strategy to reduce compensatory pathway activation relative to single-target inhibitors.	42–46
PI3K–AKT–mTOR signaling regulators	EGCG	Catechin/green tea (Camellia sinensis)	Activates AMPK, which inhibits mTORC1, and suppresses protein synthesis while inducing autophagy.	Targets metabolic dependence and invasive behavior in ER-positive and TNBC models.	49–51
	Sulforaphane	Isothiocyanate/cruciferous vegetables	Activates AMPK, inhibits AKT-mediated signaling, suppresses mTORC1, and promotes autophagy.	Targets tumor invasion and metabolic adaptation in ER-positive and TNBC models.	52–55
Multi-node PI3K–AKT–mTOR modulators	Honokiol	Biphenolic lignan/Magnolia species	Simultaneous inhibition of PI3K–AKT signaling and mTOR downstream phosphorylation leads to autophagy activation.	Demonstrates activity in therapy resistant models; potential to overcome mTOR-driven survival signaling	56–57

Note: EMT, Epithelial–mesenchymal transition; RTK, Receptor tyrosine kinase; TNBC, Triple-negative breast cancer.

Combination Strategies and Therapeutic Synergy

Due to the adaptability and complexity of breast cancer oncogenic signaling networks, PI3K–AKT–mTOR monotherapy is easily overcome by reactive feedback and acquired resistance. ⁵⁸ On the other hand, there has been increased interest in combination strategies that use phytochemicals derived from medicinal plants to increase therapeutic efficacy, reduce toxicity, and postpone resistance of the standard regimens. ⁵⁹ The pleiotropic properties of these phytochemicals enable simultaneous modulation of multiple signaling nodes, providing a strong mechanistic rationale for combining them with standard breast cancer therapies. ⁶⁰

The interaction between the PI3K–AKT–mTOR pathway and ER signaling is a major cause of endocrine resistance in hormone receptor–positive breast cancer. Several phytochemicals (quercetin, genistein, curcumin, and resveratrol) have been shown to inhibit this bidirectional signaling interaction. Based on current studies, these compounds work by inhibiting PI3K–AKT activation while also inhibiting ER-induced transcriptional activity. This mechanism can continue to induce tamoxifen or aromatase inhibitor sensitivity.^19,61,62 The combination of both inhibitors reduces the activation of ER ligand-independent and downstream survival signaling, making phytochemicals more useful as an adjunct to endocrine treatment.

CDK4/6 inhibitors are an essential part of breast cancer treatment, specifically for the ER-positive advanced cancers. However, resistance is frequently observed due to activation of the PI3K–AKT–mTOR pathway. This resistance mechanism can be overcome by phytochemicals that inhibit the activation of PI3K or AKT. Curcumin and berberine have been shown in experiments to sensitize cell cycle arrest caused by CDK4/6 inhibitors by inhibiting compensatory PI3K–AKT signaling and decreasing cyclin D1 expression.^20,63 These combinations may enable dose reduction of CDK4/6 inhibitors without compromising therapeutic efficacy, thus reducing the hematologic and gastrointestinal toxicities.

Although PI3K and mTOR inhibitors can directly suppress pathway activation, their clinical use is hampered by upstream receptor reactivation and feedback-mediated AKT signaling. Phytochemicals such as EGCG, sulforaphane, and honokiol have been shown to suppress compensatory responses through AMPK activation, inhibition of receptor tyrosine kinase signaling, and modulation of metabolic stress pathways.^64,65 Preclinical studies show that the combination of phytochemicals and mTOR inhibitors has additive or synergistic antiproliferative effects, as well as increased apoptosis and autophagy induction. ⁶⁶ Thus, combination strategies may be more effective at inhibiting pathway activation than single-agent synthetic inhibitors. Phytochemical-based combinations may provide several mechanistic advantages. These advantages include the suppression of a feedback pathway, selective targeting of parallel survival pathways, and reduced selective pressure on resistant clones. ⁵⁸ In addition, several phytochemicals have relatively favorable safety profiles, which allows them to have a reduction in the dosage of conventional agents while maintaining treatment efficacy. ⁶⁷ These findings highlight the need for more translational and clinical research on rationally designed combinations, as the current evidence remains largely limited to preclinical settings. Another important consideration is the potential for publication bias, as studies reporting positive anticancer effects of phytochemicals are more likely to be published than neutral or negative findings, which may overestimate their true therapeutic potential.

Another important consideration in combination strategies is the potential for pharmacodynamic and pharmacokinetic interactions between phytochemicals and targeted anticancer agents. Several phytochemicals have been reported to influence drug-metabolizing enzymes and transporters, including cytochrome P450 isoforms and ATP-binding cassette transporters, which may alter the systemic exposure of targeted therapies such as PI3K inhibitors, mTOR inhibitors, and CDK4/6 inhibitors. While some interactions may enhance therapeutic efficacy through synergistic pathway inhibition, others may increase toxicity or reduce drug effectiveness. Therefore, careful evaluation of drug–phytochemical interactions through pharmacokinetic and pharmacodynamic studies will be essential for safe clinical translation of these combination strategies.^76,77

Taken together, the mechanistic insights summarized in the previous sections illustrate how phytochemicals derived from medicinal plants can modulate multiple nodes of the PI3K–AKT–mTOR signaling network and potentially overcome compensatory survival pathways associated with therapeutic resistance. The conceptual framework presented in Figure 1 highlights the hierarchical organization of this signaling cascade and the points at which phytochemicals may exert inhibitory effects. However, translating these mechanistic findings into clinical applications requires overcoming significant pharmaceutical and regulatory barriers. These translational challenges—including bioavailability limitations, metabolic instability, and formulation variability—are discussed in the following section and summarized in Figure 2.

Figure 2.

Translational and Pharmaceutical Challenges in Developing Medicinal Plant-derived Phytochemicals Targeting PI3K–AKT–mTOR Signaling in Breast Cancer. Major Barriers Include Limited Bioavailability, Rapid Metabolism, Variability in Phytochemical Composition, Lack of Standardized Formulations, and Regulatory Challenges. Emerging Nanotechnology-based Delivery Systems and Pharmaceutical Optimization Strategies may Help Overcome these Limitations and Improve Clinical Translation. Figure Created by the Authors Using BioRender (BioRender.com, Version 2025).

Translational and Pharmaceutical Challenges

Bioavailability Limitations

Poor oral bioavailability is one of the major challenges in the development of phytochemical drugs. Curcumin, resveratrol, and EGCG are among many other compounds with low water solubility and intestinal absorption, resulting in low therapeutic levels in the body. ⁶⁸ Extensive first-pass metabolism further reduces systemic bioactive exposure and limits effective inhibition of PI3K–AKT–mTOR signaling in vivo. ⁶⁹ These limitations contribute to the discrepancy between encouraging in vitro findings and relatively weak in vivo efficacy.

Pharmacokinetics and Metabolism

Phytochemicals are often rapidly metabolized through phase I and phase II pathways, resulting in conjugated metabolites with variable biological activity. Interindividual differences in metabolic enzyme activity further complicate dose optimization and the reproducibility of therapeutic effects. ⁷⁰ Short plasma half-lives and rapid elimination can be significant issues for repeated target engagement in breast cancer, where sustained pathway inhibition is required to overcome resistance. ⁶⁹

Standardization Challenges

Another major obstacle is the lack of internationally standardized quality control and preparation procedures for plant extracts. Changes in the plant species, growth environment, extraction, and formulation procedure may lead to huge variations in the phytochemical composition and activity. ⁷¹ For pharmaceutical development and clinical testing, active constituents must be highly standardized and well characterized to ensure reproducibility, safety, and regulatory compliance. ⁷²

Advanced Delivery Systems

The advancement of drug delivery technology can help to overcome these limitations. Nano-formulations such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, and micellar systems have been demonstrated to improve the phytochemical solubility, stability, and bioavailability. ⁷³ These delivery systems can enhance tumor targeting, prolong systemic circulation, and support sustained inhibition of the PI3K–AKT–mTOR signaling pathway. ⁷⁴ Nano-encapsulated phytochemicals have been shown to have greater antitumor activity than free phytochemicals in breast cancer models, which is encouraging, and suggests that they are translationally viable. ⁷⁵

Regulatory Considerations

The regulatory classification of phytochemicals remains complex, as many compounds lie at the interface between nutraceutical supplements and pharmaceutical agents. Clear distinctions are needed between nutraceutical use and formal drug development pathways. Clinical translation will require well-designed pharmacokinetic studies, toxicity evaluation, and preclinical phase administration to determine safety, maximum dose, and therapeutic effectiveness. ⁷⁶ Careful consideration of drug interactions in combination with phytochemicals is also necessary when including them in a combination regimen, especially in combination with targeted therapies involving the PI3K–AKT-mTOR axis. ⁷⁷ The successful resolution of these translational and pharmaceutical issues will be critical to the clinical potential of phytochemicals as adjunctive or lead drugs in the treatment of breast cancer.

The major pharmaceutical and translational barriers that currently limit the clinical development of medicinal plant-derived phytochemicals targeting the PI3K–AKT–mTOR pathway are summarized in Figure 2. These challenges include poor bioavailability, rapid metabolism, variability in phytochemical composition, and regulatory complexities associated with herbal-derived compounds. Advances in formulation science, particularly nano-delivery systems, and standardized phytochemical preparations, may help overcome these barriers and facilitate the integration of phytochemical-based agents into modern oncology therapeutics.^73–76

Future Perspectives

Increasing evidence that medicinal plant-derived phytochemicals can regulate the PI3K–AKT–mTOR signaling pathway opens several opportunities for future research and clinical translation in breast cancer. Instead of replacing current systemic treatments, phytochemicals are best suited as adjunctive therapy, drug lead molecules, or prophylactic therapy in well-defined groups.^12,76

Phytochemicals may improve the efficacy of endocrine therapy, chemotherapy, and targeted agents by inhibiting compensatory survival signaling and reducing resistance mechanisms mediated by PI3K–AKT–mTOR signaling.^19,20 Their multiple-target activity and overall good safety profiles indicate that they may result in dose reduction of traditional medications, which may enhance tolerability and adherence to treatment in the long-term. More rational combination strategies supported by pharmacokinetic and pharmacodynamic studies should be prioritized in future research to determine the best dosing regimen and therapeutic indices. In addition to their adjunctive benefits, phytochemicals are useful lead compounds in the development of pharmaceuticals. ⁷⁸

Phytochemicals may also have preventive potential in high-risk populations, such as those who were predisposed to the disease due to inherited susceptibility, had metabolic risk factors, or had premalignant breast lesions. These compounds may be part of a cancer prevention strategy that includes regulating oncogenic signaling, metabolic stress responses, and inflammatory responses. ⁷⁹ Nonetheless, biomarker-based risk stratification must be rigorously tested before being used in clinical practice due to long-term safety, proper dosing, and risk stratification.

The incorporation of phytochemicals into precision oncology models is a promising direction in the future. Breast tumor molecular profiling (PIK3CA mutation status, pathway activation signatures, and metabolic phenotypes) can be used to identify patient subgroups that are likely to respond optimally to phytochemical-based interventions. ⁸ Finally, clinical translation will require well-constructed early-phase studies that use standard prepared formulations, validated biomarkers of target engagement, and attentive evaluation of drug-drug interactions in combination regimens. ⁸⁰

Conclusion

Although medicinal plant-derived phytochemicals demonstrate compelling mechanistic activity against the PI3K–AKT–mTOR signaling pathway, their clinical utility remains constrained by predominantly preclinical evidence, pharmacokinetic limitations, and a lack of high-quality clinical trials. These compounds should not be regarded as alternatives to established targeted therapies, but rather as adjunctive modulators or lead scaffolds capable of dampening compensatory signaling and enhancing treatment responsiveness. Nonetheless, clinical translation has limitations due to bioavailability, pharmacokinetic variability, and non-standardized formulations. Pharmaceutical optimization, particularly nano-delivery systems, and biomarker-based patient stratification, offers a practical strategy to overcome these constraints. Future research should prioritize well-designed translational studies integrating pharmacokinetic evaluation, biomarker-guided patient stratification, and standardized phytochemical formulations. Early-phase clinical trials evaluating rational combinations of phytochemicals with targeted therapies may clarify whether these compounds can enhance therapeutic responses while minimizing toxicity. Ultimately, integrating phytochemicals into precision oncology frameworks may provide a complementary strategy to improve long-term management of breast cancer patients with PI3K–AKT–mTOR pathway activation.