The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC

Abstract

Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat’s lab in 2013 has led to a recent wave of direct KRASG12C inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRASG12C mutant NSCLC. Despite this success, there remains the challenge of combating the resistance that cell lines, xenografts, and patients have exhibited while treated with KRASG12C inhibitors. This review discusses the varying mechanisms of resistance that limit long-lasting effective treatment of those direct inhibitors and highlights several novel therapeutic approaches including a new class of KRASG12C (ON) inhibitors, combinational therapies across the same and different pathways, and combination with immunotherapy/chemotherapy as possible solutions to the pressing question of adaptive resistance.

Resistance to KRAS inhibition in advanced non-small cell lung cancer

“…Two formerly promising, orally available, investigational, small molecules, LY3499446 and JNJ-74699157 (ARS-3248), were abruptly removed from the G12C inhibitor landscape ( 82 , 83 ). The discontinuation of the initial phase 1 trial of LY3499446 was due to unexpected toxicity ( 20 , 27 ).…”

“…The discontinuation of the initial phase 1 trial of LY3499446 was due to unexpected toxicity ( 20 , 27 ). Likewise, JNJ-74699157 (ARS-3248) was investigated in a phase 1 study of patients with advanced solid tumors, including NSCLC (n=5), but enrolment was terminated at just 10 patients due to dose-limiting skeletal muscle toxicities and the lack of efficacy at the lowest administered dose (100 mg) ( 83 , 85 ).…”

eIF4A dependency: the hidden key to unlock KRAS mutant non-small cell lung cancer’s vulnerability

“…Recently, covalent KRAS G12C inhibitors (KRASi), namely sotorasib (AMG510) and adagrasib (MRTX849), have been approved for the treatment of patients with advanced NSCLC carrying KRAS G12C mutations who have progressed after at least one prior line of treatment based on the CodeBreaK 100 and the KRYSTAL-1 phase I/II trials, respectively ( 6 ). NSCLC has been, so far, the most successful application of these KRASis, but somewhat also their worst disappointment.…”

“…Understanding resistance mechanisms to G12Ci and identifying biomarkers that can predict patients’ responsiveness to these agents are crucial steps to develop new strategic combination of treatments to achieve better and long-lasting responses for KRASmut NSCLC patients. Growing evidence suggests that resistance mechanisms to G12Ci exhibit an heterogenous nature ( 6 , 10 ). The main primary and acquired resistance mechanisms described up to date include, but are not limited to, loss of function mutations in tumor suppressor genes, rewiring through alternative signaling pathways, appearance of secondary KRAS mutations or upregulation of the wild-type RAS isoforms and acquisition of new pathogenic mutations in other RTK-RAS-MAPK pathways members ( 6 , 7 ).…”

“…Growing evidence suggests that resistance mechanisms to G12Ci exhibit an heterogenous nature ( 6 , 10 ). The main primary and acquired resistance mechanisms described up to date include, but are not limited to, loss of function mutations in tumor suppressor genes, rewiring through alternative signaling pathways, appearance of secondary KRAS mutations or upregulation of the wild-type RAS isoforms and acquisition of new pathogenic mutations in other RTK-RAS-MAPK pathways members ( 6 , 7 ). While numerous resistance mechanisms have been identified, the intricate nature of the G12Ci resistance landscape remains largely unexplored.…”