Beyond TKIs: Synthetic Lethal Approaches and Targeted Therapies to Watch in Lung Cancer

As numerous mutations in tumor suppressor genes can lead to loss of function, synthetic lethal approaches that can target some tumor suppressor genes represent an exciting area of investigation in lung cancer, according to Gregory J. Riely, MD, PhD.1

“The crux of it is if there are 2 genes that are required for normal cell function and one of them is mutated or deleted in a cancer if you inhibit the other, you can preferentially kill these mutated cells,” Riely explained in a presentation at the 22nd Annual Winter Lung Cancer Conference®, an event held by Physicians’ Education Resource, LCC. He added that targeted therapies in lung cancer represent a broad field beyond TKIs.

Synthetic lethality leverages drugs to target genes with complementary functions in a tumor that has acquired a specific mutation.2 By doing so, a complete disruption of the targeted genes’ functions and a subsequent defect in tumor cell viability occurs, and normal cells with the un-mutated gene are unaffected.

In his presentation, Riely highlighted inhibitors that exhibit synthetic lethality and targets of interest in the lung cancer space. Riely is the Ning Zhao and Ge Li Endowed Chair for Lung Cancer Research and vice chair of Clinical Research at Memorial Sloan Kettering Cancer Center in New York, New York.

Targeting MTAP-Deleted Tumors

MTAP is frequently lost because of its proximity to CDKN2A, and research has shown that MTAP-loss could be targeted through a synthetic lethal relationship with MAT2A and PRMT5 inhibitors.3 Although PRMT5 has been identified as a synthetic lethal target for MTAP-deleted cancers, prior PRMT5 inhibitors do not selectively target this genotype.4 Notably, approximately 15% of patients with cancer have loss of the MTAP gene, making new inhibitors of the gene an area of interest for drug development.5

“MTAP [is] often co-deleted with CDKN2A,” Riely noted, adding that “further refinement of biomarkers—next-generation sequencing panels, immunohistochemistry, etc—and further prospective trials will help to define whether this is targetable.”

BMS-986504 (MRTX1719) is an MTA-cooperative PRMT5 inhibitor that demonstrated synthetic lethality in preclinical models.4 The agent is under evaluation in a phase 1/2 study (NCT05245500) in patients with solid tumors and an MTAP deletion, and it received fast track designation from the FDA for the treatment of patients with MTAP-deleted cancers in August 2022.6

Additionally, data were presented at the 2024 ESMO Congress on the first-in-class MTA-cooperative PRMT5 inhibitor AMG 193, which selectively targets MTAP-deleted tumors.7 The investigational therapeutic preferentially binds the MTA-bound state of PRMT5, inhibiting PRMT5 completely. Findings from a phase 1 first-in-human study (NCT05094336) showed that among 17 adults with metastatic/locally advanced non–small cell lung cancer (NSCLC) and an MTAP or CDKN2A deletion, 5 achieved a partial response (PR) when treated with AMG 193 and 6 experienced stable disease. Investigators noted that the safety profile of the drug was acceptable and there was no evidence of clinically significant myelosuppression. AMG 193 is under evaluation in several studies, including in a phase 1 study (NCT06333951) as monotherapy or as part of a combination regimen for patients with NSCLC and MTAP deletions.

Shifting Gears to Examine SMARCA4 Alterations

Riely turned his attention to SMARCA4 alterations in his presentation and cited research published in Oncogene which reported that “due to the mutual exclusivity of SMARCA4 and SMARCA2 as catalytic subunits of the switching defective/sucrose non-fermentable [SWI/SNF] complex, a common approach to targeted treatment of SMARCA4-mutant cancers is synthetic lethality. This approach harnesses the simultaneous mutation of two genes to induce cell death that would otherwise not happen if one of the mutations occurred alone.”8

Notably, genes encoding subunits of the SWI/SNF chromatin remodeling complex occur in approximately 20% to 24% of cancers.9 The SWI/SNF complexes use energy generated through the hydrolysis of ATP to slide or eject nucleosomes and the complex contains either SMARCA2 or SMARCA4, which are the 2 ATP enzymatic subunits. Approximately 10% of patients with NSCLC have SMARCA4 mutations.

Data on the first-in-class intravenous SMARCA2 degrader PRT3789 were presented at the 2024 ESMO Annual Congress from the phase 1 PRT3789-01 study (NCT05639751). Among efficacy-evaluable patients with NSCLC or esophageal cancer (n = 26) who were treated with PRT3789, 29% experienced tumor shrinkage. Investigators noted the drug was generally well tolerated, and no dose-limiting toxicities were reported. Overall, 46 patients received the agent and confirmed PRs occurred in 3 patients, 1 of whom had NSCLC.

Riely noted that a “synthetic lethal approach with [the] intravenous SMARCA2 degrader leads to some tumor shrinkage. Further refinement of biomarkers and further prospective trials with new drugs will help to define whether this is targetable.”

References

1. Riely G. New TKIs: what to watch? Presented at: 2025 Winter Lung Conference; January 31-February 2, 2025; Hollywood, FL.
2. Xin Y, Zhang Y. Paralog-based synthetic lethality: rationales and applications. Front Oncol. 2023;13:1168143. doi:10.3389/fonc.2023.1168143
3. Ngoi NYL, Tang TY, Gaspar CF, et al. Methylthioadenosine phosphorylase genomic loss in advanced gastrointestinal cancers. Oncologist. 2024;29(6):493-503. doi:10.1093/oncolo/oyae011
4. Engstrom LD, Aranda R, Waters L, et al. MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP-deleted cancer. Cancer Discov. 2023;13(11):2412-2431. doi:10.1158/2159-8290.CD-23-0669
5. Promising antitumour activity presented for emerging targets in different solid tumours. ESMO Daily Reporter. September 16, 2024. Accessed February 5, 2025. https://dailyreporter.esmo.org/esmo-congress-2024/latest-news/promising-antitumour-activity-presented-for-emerging-targets-in-different-solid-tumours
6. Mirati Therapeutics reports third quarter 2022 financial results and recent corporate updates. News release. Mirati Therapeutics. November 8, 2022. Accessed February 5, 2025. https://www.prnewswire.com/news-releases/mirati-therapeutics-reports-third-quarter-2022-financial-results-and-recent-corporate-updates-301672203.html
7. Sacher AG, Villalona-Calero M, O’Neil BH, et al. Phase I dose escalation and initial dose expansion results of AMG 193: a MTA-cooperative PRMT5 inhibitor, in patients (pts) with MTAP-deleted solid tumor.Ann Oncol. 2024;35(suppl 2):S482-S535. doi:10.1016/annonc/annonc1589
8. Navickas SM, Giles KA, Brettingham-Moore KH, Taberlay PC. The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target. Oncogene. 2023;42: 2363-2373. doi:10.1038/s41388-023-02773-9
9. Guo R, Dowlati A, Dagogo-Jack I, et al. First clinical results from a phase I trial of PRT3789: a first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation. Ann Oncol. 2024;35(suppl 2):S482-S535. doi:10.1016/annonc/annonc1589