Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review

Abstract

Background and Objective Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog ( KRAS ) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. Methods In this review, we describe KRAS and the biology of KRAS -mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. Key Content and Findings KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. Conclusions The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

“…On December 12, 2022, the FDA granted accelerated marketing approval of adagrasib for use in an FDA-approved clinical trial to identify adult patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. 60 …”

Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics

“…In the last two decades, the development of small molecules as anticancer therapeutics has undergone a revolutionary transformation, particularly in the realm of molecularly targeted therapeutics, including TCIs. Those interested in delving deeper into the evolution of molecularly‐targeted agents, including those specific to mutant kinases, can explore excellent review articles on the subject (Hou et al, 2022; Kharkar, 2020; Rohilla et al, 2023; Santarpia et al, 2023).…”

Understanding KRAS for better targeting

“…Future generations of scientists will only be able to deliver better cancer treatments by gaining detailed knowledge of the cellular mechanisms that underly the disease. There is no better place for the molecular enthusiast to understand Kirsten rat sarcoma virus (KRAS) biology, signaling, and resistance than this review by Santarpia et al ( 1 ).…”

“…The KRAS mutation has been famously dubbed “undruggable” largely due to its shape—its smooth structure rendered designing inhibitors to fit onto the surface difficult to achieve and the toxicity of general inactivation of RAS in all cells is unacceptable. This review by Santarpia et al goes above and beyond—it tells us a story about the history of the KRAS protein, its molecular pathogenesis, drug targeting with attention to mutation specific inhibitors, resistance, and hints at the future potential of targeting this pathway which will need to be unlocked with more basic and clinical research ( 1 ).…”

“…This review is a bridge to understanding the significance of KRAS and is a must-read for not only laboratory scientists but also clinicians aiming to get a better grasp of the drugs they will be prescribing ( 1 ).…”