Anticancer Opportunity Created by Loss of Tumor Suppressor Genes

Abstract

Deletion of oncosuppressors occurs frequently in the cancer genome. A great deal of effort has been made to therapeutically restore the lost function of oncosuppressors, with little clinically translatable success, however. Reassuringly, besides the disappointing restoration endeavors, oncosuppressor loss can be therapeutically exploited in several other ways, such as the “synthetic lethality” strategies and the “therapeutic vulnerability” created by codeletion of neighboring genes. The study by Liu et al showed that codeletion of p53 and a neighboring essential gene POLR2A rendered colon cancer cells highly sensitive to further inhibition of POLR2A both in vitro and in vivo. In recent years, several studies have reported similar phenomenon in a wide range of cancer types. In this focus article, we will introduce several kinds of anticancer opportunities created by the loss of oncosuppressors and discuss their mechanisms. Given the frequency of oncosuppressor loss in cancer, its therapeutic exploitation rather merits further investigation and may open a new window for oncotherapy.

Although TP53 loss of function is a common and critical genetic aberration in tumorigenicity, endeavors to restore its function have gained no clinical translatable success up to now. Recent studies, however, revealed that in some cases, TP53 loss can be exploited therapeutically, as demonstrated by the study by Liu et al. ¹

This study ¹ revealed that hemizygous deletion of TP53 gene occurs in 53% of human colon cancer samples and without exception leads to hemizygous codeletion of a neighboring gene POLR2A, a phenomenon called passenger deletion (Figure 1A). POLR2A encodes an indispensable subunit of RNA polymerase II complex and thus is essential for cell survival. This passenger deletion decreased POLR2A protein abundance and therefore rendered colon cancer cells (CCCs) highly sensitive to further inhibition of POLR2A (Figure 1A). Compared with POLR2A-intact CCCs, CCCs with POLR2A hemizygosity were found to be much more sensitive to POLR2A inhibition mediated by α-amanitin (a POLR2A inhibitor) treatment or by RNA interference both in vitro and in xenograft models. Moreover, α-amanitin treatment sensitized POLR2A-hemizygous CCCs to chemotherapy agents such as 5-fluorouracil and oxaliplatin. To overcome the liver toxicity when used in vivo, the authors conjugated α-amanitin to an antibody against cancer cell-specific surface proteins. Given that hemizygous TP53 deletion is a common phenomenon in a wide range of cancer types such as ovary cancer, liver cancer, and cervical cancer, ¹ whether in these cancers the POLR2A gene is also codeleted with TP53 and the effect of its inhibition on these cancer cells merit further investigation.

Figure 1.

Anticancer opportunity created by loss of tumor suppressor genes. A, Hemizygous codeletion of tumor suppressor (GENE1) and the neighboring gene (GENE2) essential for cell survival or growth renders cancer cells highly sensitive to further inhibition of the residual GENE2 expression. B, Synthetic lethality: In normal cells, GENE1 and GENE2 are functional redundant with each other. Coinhibition of the 2 leads to cell death or growth arrest, whereas inhibition of either of them does not. In cancer cells, however, loss of function of GENE1, either by deletion or by mutation, renders cancer cells dependent on the function of GENE2, the inhibition of which leads to cell death or growth arrest. C, In normal cells, GENE2 and GENE3 are functional redundant with each other. Coinhibition of the 2 leads to cell death or growth arrest, whereas inhibition of either of them does not. In cancer cells, homologous codeletion of tumor suppressor (GENE1) and the neighboring gene (GENE2) renders cancer cells dependent on the function of GENE3, the inhibition of which leads to cell death or growth arrest.

Cancer develops from cumulative genetic aberrations such as point mutation, translocation, and copy number amplification/deletion. On one hand, these genetic aberrations lead to the activation of oncogenes and/or inactivation of tumor suppressors that cooperate to initiate cell transformation. On the other hand, these cancer-specific aberrations can be exploited to develop strategies that kill cancer cells while sparing normal ones. Deletion of tumor suppressor genes occurs frequently during tumorigenesis. In a study analyzing copy number profiles of 3131 cancer specimens across dozens of cancer types, an average of 16% of the genome was found to be deleted in cancers, including some of the tumor suppressor-encoding regions. ² Because of the frequency of tumor suppressor loss and its critical role in tumorigenesis, a great deal of effort has been made during the past decades to try to therapeutically restore the lost function of tumor suppressors, with little clinically translatable success, unfortunately.

Reassuringly, besides restoration endeavors, tumor suppressor loss can be therapeutically exploited in other ways, such as the synthetic lethality strategies ^{3 –5} (Figure 1B) and the therapeutic vulnerabilities created by passenger deletions ^1,6,7 (Figure 1A and C). In some cases, tumor suppressor loss may render cancer cells dependent on alternative pathways/proteins for survival that might be targeted to kill cancer cells specifically, a phenomenon termed synthetic lethality, as exemplified by the response of BRCA-deficient breast cancer cells to poly(ADP-ribose) polymerase inhibitor. ^3,4 A recent study ⁵ in HER-2-positive breast cancer serves as another example, which revealed that 2 kinases called PI5P4Ka and β become essential for cell growth in the absence of functional p53. Coinhibition of these 2 kinases impaired the growth of p53-null cancer cells both in vitro and in vivo, which can be counteracted by p53 restoration. ⁵ However, tumor suppressor loss does not always create suitable synthetic lethal targets. In some other cases, neighboring genes that are codeleted with tumor suppressors, also called passenger deletion, ⁶ may render therapeutic vulnerability in cancer ^1,6,7 (Figure 1A and C). Several previous studies have reported drug sensitization induced by heterozygous gene deletion in yeast. ^8,9 Nijhawan et al ⁷ studied this concept in cancer to identify genes whose collateral deletion with tumor suppressor genes render tumor-specific vulnerabilities. Another study ⁶ showed that in 1% to 5% of glioblastoma multiforme, the 1p36 tumor suppressor locus is homozygously deleted, with the ENO1 gene often included. Homozygous deletion of ENO1 gene renders tumor cells highly reliant on the function of ENO2 gene (Figure 1C), both of which encode an enzyme essential for glycolysis. Consequently, inhibition of ENO2 specifically killed ENO1 null tumor cells. ⁶ Heterogeneous deletion of ENO1 gene can also sensitize tumor cells to ENO2 inhibition but with less extent relative to homozygous deletion.

To sum up, the study by Liu et al, along with several other recent studies, demonstrated that loss of tumor suppressor genes can create novel anticancer targets, such as therapeutic vulnerabilities created by passenger deletions. ^1,6,7 Rather than trying to restore the lost functions of tumor suppressors, these studies harnessed therapeutic targets induced by loss of tumor suppressor genes and opened a new window for oncotherapy.