Targeting synthetic lethality in colorectal cancer

To the Editor: Synthetic lethality (SL) occurs when the simultaneous perturbation of two genes results in cellular death, whereas the perturbation of an individual gene alone is compatible. Colorectal cancer (CRC) is a leading malignancy, ranking third in global incidence and second in mortality. It is widely believed that most CRCs arise from the accumulations of genetic and epigenetic changes. This tumorigenic process, from normal to dysplastic epithelium to carcinoma, along with multiple genetic alterations, is referred to as the adenoma–carcinoma sequence. Meanwhile, cancers of unknown primary with a colon-cancer profile is increasingly being recognized as a distinct favorable subset.[1] Given the complex genetic landscape of CRC, there is no universal treatment for this disease, making SL a promising avenue for new therapeutic strategies. Key driver genes such as adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog (KRAS), and p53 have been identified, and targeting synthetic lethal interactions involving these genes could enhance treatment efficacy. Additionally, exploring the DNA damage repair pathways represents a vital part of developing effective SL strategies for CRC, potentially overcoming current treatment challenges. KRAS mutations are prevalent in CRC as an extensive driver in tumorigenesis and present significant treatment challenges.[2] Recent studies have indicated that dual inhibition of mitogen-activated protein kinase kinase (MEK) and cyclin-dependent kinase 4/6 (CDK4/6) may provide effective therapeutic strategies. It is worth noting that the combined inhibition of MEK and CDK4/6 showed great potential for treating KRAS-mutated CRC with the combination of binimetinib (MEK inhibitor) and palbociclib (CDK4/6 inhibitor) in treating such patients entering clinical trials in 2019 (NCT03981614).[3] A similar effect was observed with palbociclib and PD0325901 (MEK inhibitor), which also significantly reduced cell proliferation in KRAS-dependent and B-Raf proto-oncogene, serine/threonine kinase (BRAF)-mutant CRC cells.[4] SMAD family member 4 (SMAD4) acts as a tumor suppressor within the tumor growth factor (TGF)-β signaling pathway and is mutated in approximately 5.0–24.2% of CRC cases, correlating with poor prognosis.[5]SMAD4-deficient cells had a high level of MYC proto-oncogene, bHLH transcription factor (MYC), and disrupted cell cycle regulation. Bromodomain and extra-terminal motif (BET) inhibitors have shown efficacy in SMAD4-deficient HCT-116 cells, inducing G1 phase arrest by down-regulating MYC and restoring CDK inhibitory proteins.[6] Furthermore, aurora kinase A (AURKA) inhibitors have exhibited synergistic effects in SMAD4-deficient cells, leading to apoptosis through disrupted G2/M arrest and hyperactivation of the spindle assembly checkpoint.[7] Recent studies have identified several promising candidates for SL in CRC. For instance, methionine adenosyltransferase 2α (MAT2A) inhibitor blocked the growth of methylthioadenosine phosphorylase (MTAP)-deleted HCT-116 cells in vitro and in vivo. MAT2A inhibitor treatment triggered DNA damage and affected cell repair ability. The results showed that the MAT2A inhibitor induced R-loop accumulation that led to reduced replication rates and DNA damage and caused substantial alterations in RNA splicing downstream of protein arginine methyltransferase 5 (PRMT5) by affecting PRMT5 activity. Moreover, the patient-derived xenograft study also indicated that the loss of fanconi anaemia (FA) complex activity might cooperate with MAT2A inhibition-induced DNA damage. Certain critical DNA damage regulators with detained introns (DI) were affected by MAT2A inhibition, suggesting that DNA damage dysregulation plays an important role in the antiproliferative activity of MAT2A inhibition.[8] Vacuolar protein sorting 4 homolog B (VPS4B), encoding an adenosine triphosphatase (ATPase) involved in the endosomal sorting complexes required for the transport (ESCRT) machinery, is often deleted in CRC, and its paralog VPS4A was identified as an SL interactor. Dual knockdown of VPS4A and VPS4B (VPS4A + B) significantly reduced HCT-116 cell proliferation and suppressed tumor growth in mouse xenografts. VPS4A + B depletion activated multiple cell death pathways, including nuclear factor kappa B (NF-κB) subunit 1 signaling and further caspase activation, accompanied by the release of immunomodulatory molecules and antitumor responses.[9] Additional research has uncovered synthetic lethal interactions involving other genes. AT-rich interactive domain 1A (ARID1A) deficiency has been associated with increased sensitivity to AURKA inhibitors, whereas RAD54B-deficient cells are hypersensitive to poly ADP-ribose polymerase (PARP) inhibitors, indicating their potential as therapeutic targets.[10] DNA repair deficiency is common in tumor cells, and it can promote tumorigenesis with six primary pathways.[11] Among the key components involved in DNA damage repair (DDR), ataxia telangiectasia and Rad3-related (ATR) kinases have long been considered potential therapeutic targets after the success of PARP inhibitors. DNA primase subunit 1 (PRIM1)[12] and DNA polymerase delta 1 catalytic subunit (POLD1)[13] exhibited SL to ATR, enhancing the sensitivity of CRC cells to ATR inhibitors. The combination of WEE1 G2 checkpoint kinase (WEE1) and ATR inhibitors induced antitumor immunity and inhibited tumor growth in vitro and in vivo.[14] The landscape of CRC treatment is rapidly evolving, particularly with advancements in next-generation sequencing and functional genomic approaches. SL is gaining traction and many candidates are moving into clinical trials. Notably, PARP inhibitors are becoming first-line maintenance therapies, and camonsertib, ceralasertib, and other ATR inhibitors are currently undergoing clinical trials. Other candidates, such as PRMT5, MAT2A, and WEE1 inhibitors have also been explored [Table 1]. Table 1 - Selected novel synthetic lethality-based inhibitors in clinical trials for colorectal cancer treatment. Target Drug Pharmaceutical company Clinical trials Registration number Study phase Conditions Recruiting status ATR Camonsertib Repare Therapeutics NCT04497116 Phase 1/2a Advanced solid tumors Recruiting Ceralasertib AstraZeneca NCT03428607 Phase 2 Relapsed small cell lung cancer Completed NCT05450692 Phase 3 Non-small cell lung cancer Recruiting Bertzosertib Merck KGaA NCT03896503 Phase 2 Relapsed small cell lung cancer Active, not recruiting NCT03517969 Phase 2 Metastatic castration-resistant prostate cancer Active, not recruiting ATRN-119 Atrin Pharmaceuticals NCT04905914 Phase 1/2a Advanced solid tumors Recruiting ART-0380 ArtiosPharma NCT04657068 Phase 1/2a Advanced or metastatic solid tumors Recruiting PRMT5 GSK3326595 GlaxoSmithKline NCT04676516 Phase 2 Early stage breast cancer Completed AMG 193 Amgen NCT05094336 Phase 1/1b/2 Advanced MTAP-null solid tumors Recruiting MAT2A IDE397 IDEAYA Biosciences NCT04794699 Phase 1/2 Tumors harboring MTAP deletion Recruiting WEE1 Adavosertib Merck & Co NCT04590248 Phase 2 Recurrent or persistent uterine serous carcinoma Completed ZN-c3 Zentalis Pharmaceuticals NCT05743036 Phase 1/2 Metastatic CRC Not yet recruiting IMP7068 Impact Therapeutics NCT04768868 Phase 1 Advanced solid tumors Recruiting Debio 0123 Debiopharm International SA NCT05109975 Phase 1 Advanced solid tumors Recruiting SY-4835 Shouyao Holdings (Beijing) Co. LTD NCT05291182 Phase 1 Advanced solid tumor Recruiting ATR: Ataxia telangiectasia and Rad3-related; CRC: Colorectal cancer; DDR: DNA damage repair; MAT2A: Methionine adenosyltransferase 2a; MTAP: Methylthioadenosine phosphorylase; PRMT5: Protein arginine methyltransferase 5; WEE1: WEE1 G2 checkpoint kinase. With the development of technology, the vulnerability of CRC cells in response to DNA damage and other synthetic lethal interactions has been revealed. Further research focusing on the discovery of SL gene pairs and novel SL drugs in clinical trials is required. With many candidate SL targets, the translation of these uncovered SL interactions into the clinical treatment of CRC has become a current challenge. Funding The study was supported by grants from the Project of Science and Technology Department of Sichuan Province (No. 2023NSFSC1928), the Project of State Administration of Traditional Chinese Medicine of China (No. ZYYCXTD-D-202209), the Fundamental Research Funds for the Central Universities, and the Project of Sichuan Provincial Administration of Traditional Chinese Medicine Sichuan (No. 2022C001). Conflicts of interest None.