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Abstract

Targeted therapies have significantly improved the prognosis and productivity of non-small-cell lung cancer (NSCLC) patients carrying driver mutations, but drug resistance is inevitable. Histological transformation, an important resistance mechanism, is often manifested as transformation into small-cell lung cancer, large-cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma. The mechanisms involved are complex, including RB1/TP53 inactivation, epithelial–mesenchymal transition, and microenvironmental changes. Post-transformation tumors are often more aggressive and drug-resistant, with limited therapeutic options and poorer prognosis. In this paper, we systematically review the histological transformation types, molecular mechanisms, and therapeutic strategies of NSCLC after resistance to targeted therapy, with the aim of providing a reference for clinical decision-making and promoting the development of individualized therapy.

Keywords

drug resistance histologic transformation non-small-cell lung cancer targeted therapy treatment strategy

Introduction

In China, approximately 61.4% of patients with non-small-cell lung cancer (NSCLC) harbor driver gene mutations.¹ According to the National Comprehensive Cancer Network guidelines, routine testing is recommended for mutations in genes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), Kirsten rat sarcoma viral oncogene (KRAS), and targeted therapies have become the standard of care for driver gene-positive advanced NSCLC and have shown good efficacy. However, the development of drug resistance remains inevitable. For example, the median progression-free survival (PFS) of the first-line treatment with third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is only about 20 months.² Current studies indicate that common mechanisms of TKI resistance include secondary mutations in driver genes (e.g., EGFR T790M mutation), bypass activation (e.g., mesenchymal epidermal transforming factor (MET) gene amplification), and histologic transformation.³

Histologic transformation refers to the process by which tumor cells alter their histologic subtype. In NSCLC, the main types of histologic transformation include small-cell lung cancer (SCLC), large-cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SCC), and sarcomatoid transformation.⁴ Among these, SCLC transformation is the most common. Histological transformation not only affects the biological behavior of tumors, but may also lead to the failure of existing targeted therapies, thus limiting the therapeutic efficacy and significantly shortening the survival of NSCLC patients.⁵ Although many studies have aimed to elucidate the underlying mechanisms, comprehensive understanding remains limited, and standardized therapeutic approaches are lacking after transformation.⁶ Therefore, this review aims to provide a comprehensive summary of the types, mechanisms, and therapeutic strategies of histologic transformation occurring in driver gene-positive NSCLC after resistance to targeted therapy for clinical reference. Table 1 summarizes the clinical features, molecular alterations, and therapeutic outcomes across different transformation subtypes of driver gene-positive NSCLC.

Table 1.

Summary of clinical characteristics, common mutations, and treatment responses in histologic transformation subtypes of driver gene-positive NSCLC.

Transformation type	Occurrence frequency	Clinical features	Common driver mutations	Molecular features	Chemotherapy	TKI	ICI	Recommended regimens	Prognosis	Evidence type
SCLC	3%–14%	Young, non/little smokers	EGFR, ALK, ROS1	RB1/TP53 loss, EGFR downregulation	EC regimen, limited ICI benefit	Local treatment can be combined	Few reports valid	Platinum-etoposide ± TKI/ICI	Poor (mOS ~9–11 mo)	Case reports, Retrospective study
LCNEC	<5%	Middle-aged and older,	EGFR-T790M, STK11	TP53/RB1, Neuroendocrine markers, MYC/PTEN	Poor to chemo alone	There are cases to support.	No large-scale studies	LCNEC-like chemo ± TKI	Poor (mPFS ~1.5–2.1 mo)	Small studies, case reports
SCC	<2%	Mostly females	EGFR, KRAS	PI3K/AKT/mTOR alteration, LKB1 loss, PTEN	Mixed; chemo or ICI in PD-L1+	Mixed response	Higher PD-L1 is beneficial	Chemo ± TKI or ICI	Generally poor	Very limited evidence
Sarcomatoid	Extremely rare	Late stage rapid progression	EGFR, ALK	MET amplification, PD-L1+	Very poor	Limited effect	A small number of early studies	Chemo ± epigenetic/ICI (exp.)	Very poor (mOS ~2.5 mo)	Case reports only

ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; KRAS, Kirsten rat sarcoma viral oncogene; LCNEC, large-cell neuroendocrine carcinoma; mo, months; mOS, median overall survival; mPFS, median progression-free survival; NSCLC, non-small-cell lung cancer; PD-L1, Programmed cell death ligand 1; PTEN, phosphatase and tensin homolog deleted on chromosome ten; ROS1, reactive oxygen species-1; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer; STK, serine-threonine kinase; TKI, tyrosine kinase inhibitors.

Mechanisms for histological transformation

SCLC transformation

Approximately 3%–14% of patients with EGFR-mutant NSCLC transform into SCLC after treatment with EGFR-TKI, which usually occurs within 14–26 months after TKI therapy, with a median transformation time of 18 months.⁷ It has been reported that transformed SCLC can also occur in NSCLC patients with ALK, reactive oxygen species-1, rearranged during transfection, and Neuro Trophin Receptor Kinase fusion genes and following TKI treatment, as well as in NSCLC patients following chemotherapy and immunotherapy.^8,9

Zakowski et al.¹⁰ were the first to report this phenomenon, describing a 45-year-old female never-smoker with EGFR-mutated adenocarcinoma who developed SCLC on re-biopsy after 18 months of erlotinib treatment.¹⁰ Lingling et al. also reported a case of ALK-positive NSCLC transforming into SCLC harboring an ALK V1180L mutation. These cases highlight the complex and dynamic genetic changes in tumors under therapeutic pressure and underscore the need for continuous monitoring and individualized treatment strategies.¹¹

The underlying mechanism of transformed SCLC remains to be elucidated, with the following hypotheses being postulated. Firstly, the tumor cell heterogeneity hypothesis is posited: the pathological diagnosis is typically based on small specimens, such as a puncture biopsy, and it is acknowledged that this has limitations and cannot fully reflect the overall situation of the tumor tissues. That is, there is a possibility of the simultaneous existence of two components, namely, NSCLC and SCLC.¹² Secondly, the hypothesis concerning tumor stem cells posits that cells carrying sensitive mutant tumor cells have the potential to differentiate into neuroendocrine tumor cells themselves. It has been demonstrated that exposure to TKI is associated with an elevated risk of transformation into SCLC. A third hypothesis, the molecular mechanism hypothesis, posits that during TKI treatment, double deletion mutations of the oncogenes RB1 and TP53 emerge and exert a significant influence on the process of SCLC transformation.⁷

Although transformed SCLC shares many features with classical SCLC—including pathomorphology, molecular characteristics, clinical presentation, and treatment sensitivity—it differs in some important ways. Firstly, primary SCLC is strongly associated with smoking, whereas patients with SCLC transformation tend to be younger and often occur in nonsmokers or light smokers.⁷ Secondly, small-cell transformation can occur in a variety of circumstances, such as treatment stress, chemotherapy, and radiotherapy, and is most common in patients with driver gene-positive NSCLC, with NSCLC to SCLC transformation occurring much less frequently in nondriver gene-positive patients.¹³

Most transformed SCLCs retain the original EGFR mutations, as observed in multiple studies and acquire the classical features of SCLC, such as concurrent inactivation of RB1 and TP53, decreased EGFR protein expression, and increased sensitivity to BCL-2 inhibition.^7,14 According to Lee et al.¹⁵ RB1 and TP53 inactivation is necessary for the transformation of adenocarcinoma to small-cell carcinoma after resistance to EGFR-TKI treatment. When RB1 and TP53 genes were completely inactivated, the patient had a 42-fold increased risk of SCLC transformation.¹⁶ This finding not only provides a molecular level explanation for the transformation of the tumor type in this patient, but also reaffirms the central role of TP53 and RB1 gene inactivation in increasing the risk of SCLC transformation.

Loss of RB1 protein expression is a consistent feature in SCLC transformation. In cases where patients with EGFR-mutated adenocarcinoma transformed into SCLC, we found that almost all of them were accompanied by loss of the RB1 gene.¹⁷ Matthew J evaluated biopsy cells from patients with drug-resistant EGFR-mutated lung cancer and found that the expression of RB1 was generally absent in SCLC patients. However, the loss of RB1 alone was not sufficient to develop small-cell tumors; a combination of other factors is also needed.¹⁸

Transcription factor achaete-scute homolog 1 (ASCL1), regulated by the NOTCH signaling pathway, also plays an important role. Downregulation of NOTCH2 and upregulation of ASCL1 and CD56 during transformation promote CDK5 activation, leading to RB inactivation via phosphorylation.^19,20 Niederst et al.¹⁴ demonstrated that transformation is often accompanied by both RB1 inactivation and EGFR downregulation, with RB1 loss enhancing neuroendocrine differentiation and further suppressing EGFR expression.

Additional studies have found reduced EGFR protein levels and resistance to EGFR-TKIs post-transformation, alongside mutations in PIK3CA,²¹ BRAF, WNK1,²² ETV1,²³ upregulation of SPP1,²⁴ REST inactivation,²⁵ and mutations in NFKBIA, NKX2-1, CCNE1, RBM10, IRS2 and GNAS.⁹ These findings provide valuable insight into the molecular events driving SCLC transformation.

LCNEC transformation

Histologic transformation from NSCLC to LCNEC has attracted growing attention. In one reported case, an EGFR-T790M-positive patient transformed to LCNEC without detectable T790M after Osimertinib treatment.²⁶ Several factors may contribute to this transformation. First, as the tumor evolves, accumulated genetic alterations may render initial driver mutations insufficient to sustain tumor progression, necessitating additional genomic changes. Second, the tumor microenvironment—including immune cells, fibroblasts, and secreted cytokines—may modulate tumor cell behavior and induce phenotypic shifts.²⁷

Genomic studies of LCNEC transformation have identified frequent mutations in TP53, RB1, Kelch-like ECH-associated protein 1 (KEAP1), MYC, and phosphatase and tensin homolog deleted on chromosome ten (PTEN),²⁸ with Serine-Threonine Kinase 11 (STK11) also commonly altered. Furthermore, neuroendocrine differentiation in NSCLC has been associated with the changes in expression of apoptosis-related genes such as BAG3, caspase-3, and survivin.²⁸ Disruption of these regulatory pathways may enable tumor cells to escape growth control and promote transformation into the LCNEC phenotype.²⁹

While mutations in TP53, RB1, and other regulators of neuroendocrine differentiation have been recurrently identified, the exact triggers and clonal evolution leading to LCNEC transformation remain poorly understood. The rarity of reported cases and limited mechanistic studies mean this remains an emerging area of investigation. These observations emphasize the importance of molecular and microenvironmental interactions in histologic plasticity, highlighting the need for further research into predictive markers and therapeutic targets in LCNEC-transformed NSCLC.

SCC transformation

Transformation to SCC is the least common type of histological transformation occurring after drug resistance in NSCLC, and there are very few case reports on such transformations, most of which involve EGFR-sensitive mutations (e.g., 19Del, L858R), and the majority of patients described in the available data were female (72.7%), with a median age of 62 years (range of 40–79 years),^30,31 and a small percentage of cases have also been reported in association with other driver genes such as EGFR L861Q, KRAS G12D mutation, etc. Jiang et al.³² investigated gene mutations in ADC-to-SCC transformation and found that the number of mutations in SCC transformed tumors was much higher than in ADC tumors and that EGFR L861Q, BEND5 K182fs, and TP53 H61R were present in both ADC and SCC tumors.

Mechanistically, SCC transformation is believed to involve several pathways. Structural variations, particularly gene copy number alterations stemming from chromosomal instability, can alter ubiquitin-specific proteases³² and immune-related signaling, promoting resistance and epithelial–mesenchymal transition (EMT). LKB1 inactivation is another proposed mechanism,³³ with animal models showing spontaneous ADC-to-SCC transformation in the context of LKB1 loss and KRAS activation. Genomic changes affecting the PI3K/AKT/mTOR pathway have also been observed in transformed SCCs,³⁴ including alterations in PTEN, LKB1, PIK3CA, and RICTOR. Collectively, these alterations may provide adaptive advantages allowing tumor survival under EGFR-TKI pressure and completion of histologic transformation.³⁵ Much of the current understanding is derived from animal models and case reports, and further clinical-genomic correlation is needed to validate these mechanisms.

Sarcomatoid transformation

Sarcomatoid carcinoma is a rare but aggressive subtype of NSCLC that can emerge through histologic transformation, typically in the setting of EGFR or ALK mutations. Reported cases are few, but suggest rapid progression and poor prognosis. Lee and Chang³⁵ reported a patient with adenocarcinoma that transformed to squamous carcinoma after 15 months of chemotherapy, then transformed to sarcomatoid carcinoma after 11 months of treatment, and finally deteriorated rapidly and died after 2 months. Hsieh et al.³⁶ studied six patients with transformation of adenocarcinoma of the lung to sarcomatoid carcinoma after treatment with TKI, and the median survival time after transformation was only 2.5 months.

NSCLC patients undergo sarcomatoid transformation after drug resistance, in which EMT plays an important role. EMT is a biological process in which epithelial cells are transformed into mesenchymal cells through a specific program. Epithelial cells lose their epithelial phenotype, such as cell polarity and connection to the basement membrane, and acquire a mesenchymal traits including increased migration and invasion, resistance to apoptosis, and ability to degrade the extracellular matrix. Therefore, this change makes the prognosis of such cancers poor. However, studies on its specific mechanism in the transformation of NSCLC to sarcoma are limited. The study by Hsieh et al.³⁶ revealed that sarcoma-like transformation is often closely associated with MET gene copy number variation and high expression of c-MET protein, and noted that the majority of cases are accompanied by overexpression of programmed cell death ligand 1 (PD-L1). Similarly, MET gene amplification was observed in sarcomatoid transformation cases reported by Zheng. Therefore, we proposed the hypothesis that sarcoma-like transformation might be associated with MET amplification and PD-L1 overexpression.³⁵ Current insights into sarcomatoid transformation largely rely on a few clinical cases and preclinical models. Given its rarity, further studies are needed to clarify the molecular drivers and to establish effective treatment approaches for sarcomatoid-transformed NSCLC.

Therapeutic strategies for histologic transformation

Histologic transformation represents a complex and challenging clinical scenario in the treatment of NSCLC. Among these, SCLC transformation has attracted much attention due to its rapid disease progression and poor prognosis. Several studies have described the clinical features and therapeutic challenges of SCLC transformation, emphasizing the need for timely adjustment of therapeutic strategies after transformation. In addition, other transformation types such as LCNEC, SCC, and sarcomatoid carcinoma, though less frequent, also challenge existing treatment paradigms. In this section, treatment strategies for different types of histologic transformation will be discussed in depth, including current standard treatments, emerging therapies, and future research directions, with the aim of providing a scientific basis for clinical decision-making. The clinical characteristics of reported cases are summarized in Table 2.

Table 2.

Summary of reported cases of histologic transformation in driver gene-positive NSCLC: clinical characteristics, treatment strategies, and outcomes.

Age/gender	Smoking history	Initial pathological diagnosis	Driving gene	Stage	Pre-conversion treatment	Conversion type	Conversion time month	Post-translational therapy	Treatment effect	OS month	PFS month	Reference
77/F	—	NSCLC	ALK	IVB	1L: Erlotinib 2L: Radiotherapy	SCLC	12	Atrlizumab + etoposide + carboplatin	PR	21	/	4
53/M	+	NSCLC	ALK		Alectinib	SCLC	8	Etoposide/platinum		/	/	11
51/F	—	ADC	/	IIIA	Cisplatin + Pemetrexed	SCC	8	Docetaxel	SD	/	4	12
48/M	+	NSCLC	EGFR	IIB	Carboplatin + Gemcitabine	SCLC	62	Irinotecan + carboplatin	PR	88	3	20
79/F	—	SCC	EGFR	IVB	Carboplatin + Gemcitabine; Erlotinib; Osimertinib	LCNEC	89	Carboplatin + etoposide	PD	94	/	27
79/F	—	NSCLC	EGFR	IV	Carboplatin + Gemcitabine; Osimertinib	LCNEC	69.1	Carboplatin + etoposide	PD	94	1.4	27
72/F	—	ADC	EGFR	IVA	Gefitinib	SCLC	15	Irinotecan + Carboplatin + Erlotinib	PR	/	15	29
54/M	—	NSCLC	EGFR	IB	Gefitinib	SCC	117	Amonatinib	SD	125+	9	32
61/M	—	NSCLC	EGFR	IV	Gefitinib	SCC	28	Paclitaxel + carboplatin + pimAb	PR	52+	8	33
28/M	—	NSCLC	EGFR	IVA	1L: Gefitinib; 2L: Bevacizumab, Pemetrexed, Cisplatin	SCC	38	Sintemab + allotinib	PR	52	15	36
44/M	—	ADC	EGFR		Cisplatin + Pemetrexed; Osimertinib	SCC; EMT	15; 11	/	SD	56	/	37
36/M	+	ADC	ROS1	IVA	Cisplatin + Pemetrexed + Bevacizumab	EMT	78	/	SD	81	3	38
41/M	—	ADC	EGFR	IVB	Gefitinib + Cisplatin	EMT	88	/	SD	89	1	38
76/F	—	ADC	EGFR	IVA	Gefitinib + Otinib	EMT	39	/	SD	43	/	38
65/F	+	NSCLC	/	IA	Gemcitabine + Carboplatin	SCLC	86	Etoposide + cisplatin	PR	102	15	39
50/M	+	NSCLC	EGFR	IVA	1L: Erlotinib 2L: PD-L1 inhibitor + Pemetrexed + Carboplatin	SCLC	13.1	Etoposide + carboplatin	PR	/	/	42
59/F	+	NSCLC	EGFR		Gefitinib; Ossitinib; Afatinib combined with Bevacizumab	SCLC	38	Cisplatin + etoposide; +Continuous use of oseltamivir; paclitaxel	PR	60	6	52
74/M	+	NSCLC	EGFR	IIIB	Gefitinib	SCLC	12	Etoposide + cisplatin	PD	18		53
57/M	—	NSCLC	EGFR	IV	Erlotinib	LCNEC	50	Cisplatin + etoposide	PR	61	1.4	54
33/M	—	NSCLC	EGFR	IV	Pemetrexed + Cisplatin; Erlotinib	LCNEC	12	Cisplatin + etoposide + erlotinib	PD	15.6	2.1	55
61/M	+	ADC	/	IIB	Carboplatin + Paclitaxel	SCC	9	Cisplatin + gemcitabine	PR	/	12+	57

1L, first-line treatment; 2L, second-line treatment; ALK, anaplastic lymphoma kinase; EGFR, epidermal carcinoma growth factor receptor; EMT, sarcoma; F, female; LCNEC, large-cell neuroendocrine carcinoma; M, male; NSCLC, non-small-cell lung cancer; OS, overall survival; PD, disease progression; PFS, progression-free survival; PR, partial remission; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer; SD, stable disease; ADC, Antibody–Drug Conjugate.

Therapeutic strategies for SCLC transformation

Transformed SCLC is typically associated with aggressive disease behavior and poor outcomes, Gu Y et al. conducted a multicenter retrospective study evaluating the clinical outcomes of 48 cases of EGFR-mutant non-small-cell lung cancer that underwent SCLC transformation between 2005 and 2017, with a median time to SCLC transformation of 16 months, and a median overall survival (mOS) after transformation of 9 months; Marcoux et al.⁷ reported another multicenter retrospective study evaluating the clinical outcomes of 58 adenocarcinomas transformed into SCLC, with a median survival after transformation of 10.9 months, similar to the series of Gu Y et al.³⁷

Due to the lack of prospective randomized trials, treatment decisions for transformed SCLC are largely based on disease progression patterns. For transformed SCLC with systemic rapid progression after EGFR-TKI resistance, standard SCLC chemotherapy regimens are recommended. In cases of isolated lesion progression, continuation of EGFR-TKIs combined with local therapy or SCLC chemotherapy may be considered. SCLC patients with systemic slow progression can be treated with a standard SCLC chemotherapy regimen ± EGFR-TKI.^38,39 For treatment recommendations in the latter two cases, the sources of evidence are mainly case reports and retrospective studies with small samples, and the optimal treatment strategy remains to be further investigated.

Etoposide combined with platinum-based agents (EC regimen) remains the most widely used approach, demonstrating tumor shrinkage in many cases. However, the overall prognosis remains poor, with an mOS ranging from 6 to 10.9 months.^40,41 Some reports suggest that combining cytotoxic chemotherapy with TKIs may improve objective response rate and PFS,^42,43 though without significant survival benefit.

The role of immune checkpoint inhibitors (ICIs) in transformed SCLC is controversial. While a single-center retrospective study reported prolonged survival with ICI-based combination therapy,⁴⁴ other multicenter studies found limited efficacy.^7,45,46

Although there is an ongoing prospective, single-arm, multicenter study aimed at further evaluating the efficacy of long-term immune maintenance after immune-combination chemotherapy,¹⁶ the exact efficacy and therapeutic value of ICIs in transformed SCLC as a whole has not yet been clarified. Therefore, ICIs are not routinely recommended in current practice and require further validation in large-scale clinical trials.

Despite limited progress in targeted therapy for SCLC, several novel agents are under investigation. Promising strategies include the use of DLL3-targeting antibodies combined with PARP inhibitors,⁴⁷ BCL-2 family inhibitors, and AURKA inhibitors such as Alisertib in combination with Osimertinib.⁴⁸ Furthermore, Serplulimab plus chemotherapy is currently being explored in clinical trials for untreated transformed SCLC.⁴⁹

Given the possibility of tumor heterogeneity post-transformation, re-biopsy remains crucial to identifying the dominant histologic subtype and tailoring treatment accordingly.⁵⁰ Serum neuron-specific enolase (NSE) elevation and rapid resistance to EGFR-TKIs may serve as early indicators of SCLC transformation.^43,51

In summary, transformed SCLC has become a difficult clinical treatment with its rapid disease progression and poor prognosis. These research advances not only deepen our understanding of SCLC but also provide more options and strategies for future clinical treatment. Figure 1 provides a visual summary of clinical decision-making pathways in cases of histologic transformation, integrating molecular testing, biopsy confirmation, and treatment options.

Figure 1.

Treatment decision flowchart for histologic transformation in driver gene-positive NSCLC.

Therapeutic strategies for LCNEC transformation

LCNEC transformation is relatively rare, and the limited number of reported cases has restricted our in-depth study of the biological mechanisms and effective treatment strategies for this type of transformation, and a consensus on the optimal treatment has not yet been reached. Baglivo et al.⁵² demonstrated that even in the absence of a known targeted genetic variant, “LCNEC-like” chemotherapy regimens can still provide clinical benefits to patients, even in the absence of known targeted genetic variants. In order to achieve precision medicine for LCNEC, Zhou et al. showed that driver gene changes in LCNEC can be identified using NGS technology, offering the possibility of targeted therapy in advanced cases. For example, Selinexor prevents the overexpression of Sex determining region Y-box 2 (SOX2) in tumor cells by blocking the function of Exportin 1, which in turn inhibits LCNEC transformation and improves the duration of the effect of targeted therapy.⁵³ Although platinum-containing chemotherapy remains a common clinical treatment, it is not as effective, with a median PFS of only 1.5 months in transformed patients.²⁶ Preliminary evidence suggests that combining chemotherapy with a TKI may be more effective than chemotherapy alone, but more studies are needed to confirm this. For example, Liu et al.⁵⁴ reported a median PFS of 2.1 months in a patient with NSCLC carrying an EGFR mutation who was treated with chemotherapy plus erlotinib after undergoing LCNEC transformation. However, studies on such histological transformations are still scarce, and future large-scale prospective studies are needed to evaluate the effectiveness of different treatments.

Therapeutic strategies for SCC transformation

There are no established treatment guidelines for SCC transformation. Roca et al.⁵⁵ reported a median survival of only 3.5 months in patients with EGFR-mutated NSCLC after SCC conversion in a pooled analysis. Based on available case reports of SCC transformation, three EGFR-mutated cases were continued with first-generation TKIs, with a wide variation in response. Four received Carboplatin-based chemotherapy, with moderate efficacy of Pemetrexed and Vincristine and ineffectiveness of Gemcitabine. Two additional T790M-mutated patients started third-generation EGFR TKIs with good efficacy (one patient received Osimertinib and achieved PR, and one received Bosutinib for more than 10 months).

In the case of Ye et al.³¹ study, a patient with EGFR L858R-mutated lung adenocarcinoma who developed localized SCC transformation after 27 months of gefitinib treatment achieved 8-month PFS by integrating multiline chemotherapy with immunotherapy.

In addition, a case of EGFR-mutated pulmonary ADC patient transformed into SCC with high PD-L1 expression after resistance to targeted therapy, radiotherapy, and chemotherapy also showed great efficacy by immunotherapy combined with anti-angiogenic drugs, which may be due to the high expression of PD-L1 and the synergistic effect of ICIs and anti-angiogenic drugs, and NSCLC patients with EGFR-TKI resistance often have higher levels of PD-L1 expression than those before drug resistance.³⁴ PD-L1 expression levels tend to be higher than the pre-resistance levels.³⁴ In addition, inhibitors targeting the pathway PI3K/AKT/mTOR may help to overcome TKI resistance and block or reverse transformation, but there are fewer relevant studies, and a systematic evaluation in clinical trials is urgently needed.

In conclusion, NSCLC transformation to squamous carcinoma is rare in clinical practice, and the optimal treatment for this condition should be evaluated in further studies.

Therapeutic strategies for sarcomatoid transformation

Cells with sarcomatoid transformation usually show loose intercellular junctions, large size, highly eosinophilic cytoplasm, and diverse nuclear morphology, and these cells often show strong positivity for poikilocyte protein and lack of calreticulin E expression on immunohistochemical testing. The diagnosis relies on changes in these molecular markers rather than histologic examination,^56,57 and clinical cases of sarcomatoid transformation that can be readily observed by pathologists are very rare.

The phenomenon of sarcoma-like transformation is thought to be associated with a reversible state of reduced drug sensitivity prior to the onset of terminal resistance, and its persistence is associated with altered chromatin status, such as high expression of histone demethylase H3 Lys4 and other chromatin-modifying enzymes. The use of epigenetic therapies such as histone deacetylase inhibitors may restore sensitivity to EGFR-TKIs in preclinical models; however, further trials are needed to test these hypotheses.

In addition to epigenetic therapies, combination therapeutic regimens based on active vitamin D3 (1,25(OH)2D3) are currently being explored in preclinical models in an extreme manner in order to assess their therapeutic efficacy against drug resistance associated with sarcomatoid transformation.¹⁷ In addition, it has been shown that the ability to target the B-cell lymphoma protein family and activate the apoptotic pathway through the use of BCL-2 homology 3 mimics (BH3) holds promise for overcoming the problem of drug resistance associated with the process of sarcoma-like transformation. In addition, pharmacological inhibitors of the NOTCH1-signaling pathway are being explored with the aim of being able to reestablish sensitivity to EGFR TKIs.⁴⁸ These studies provide new strategies and directions for overcoming sarcoma-like transformation in NSCLC.

Outlook

Timely identification of histologic transformation is critical for guiding appropriate therapeutic strategies in NSCLC.¹⁷ In particular, SCLC transformation should be suspected in EGFR-mutant patients who exhibit rapid clinical progression, the occurrence of resistance to EGFR-TKIs, or a sudden rise in serum neuroendocrine markers such as NSE or progastrin-releasing peptide. In such cases, repeat biopsy is essential to confirm transformation and inform subsequent treatment decisions.

Emerging combination regimens may offer potential to delay or prevent histologic transformation by targeting multiple resistance pathways. For example, osimertinib plus chemotherapy, as evaluated in the FLAURA2 trial, demonstrated improved PFS and deeper responses compared to monotherapy, potentially suppressing subclonal evolution.² Similarly, the combination of amivantamab and lazertinib, studied in the MARIPOSA trial, provides dual inhibition of EGFR and MET signaling, which may reduce lineage plasticity under therapeutic pressure. Although transformation rates have not been established as a predefined endpoint, future trials incorporating longitudinal tissue or liquid biopsy analyses could help determine their impact on transformation risk.

As histologic transformation remains one of the mechanisms of acquired resistance in driver gene-positive NSCLC, ongoing research is needed to clarify its molecular underpinnings and identify predictive biomarkers. In parallel, treatment approaches should increasingly integrate molecular profiling, combination therapies, and multimodal strategies—such as early use of local ablative techniques—to delay or mitigate transformation. These efforts may ultimately improve long-term outcomes in this challenging subset of patients.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Yanjun Xu

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Histologic transformation after targeted therapy resistance in driver gene-positive NSCLC: mechanisms and therapeutic challenges

Abstract

Keywords

Introduction

Mechanisms for histological transformation

SCLC transformation

LCNEC transformation

SCC transformation

Sarcomatoid transformation

Therapeutic strategies for histologic transformation

Therapeutic strategies for SCLC transformation

Therapeutic strategies for LCNEC transformation

Therapeutic strategies for SCC transformation

Therapeutic strategies for sarcomatoid transformation

Outlook

Footnotes

Acknowledgements

Declarations

ORCID iD

References