Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies

Abstract

Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.

KRAS in NSCLC: State of the Art and Future Perspectives

“…Indeed, KRAS G13D was the most frequently observed on-target mutation in sotorasib-resistant clones (23%), while KRAS Q99L represented the most common mutation after adagrasib exposure (52.8%). Of note, sotorasib-and adagrasib-resistant clones were both associated with Y96D and A59S point mutations [ 31 ]. Importantly, a new KRAS inhibitor RM-018 proved preclinical evidence of efficacy in overcoming secondary acquired KRAS G12C/Y96D mutations [ 31 , 81 ], although these data need to be validated in prospective clinical trials.…”

“…KRAS G12C weakens the interaction with PI3K, and the bulky aspartic acid in the G12D prevents the formation of the binding with RelA/RelB [ 30 ]. Besides NSCLC, KRAS mutations are also frequent in other tumor types, such as pancreatic and colorectal adenocarcinoma (88% and 50% of all cases, respectively) [ 28 , 31 ], with KRAS G12D mutations being the most common alteration among these histotypes (32% and 46% of all cases, respectively) [ 32 ].…”

KRAS Inhibitors and Target Engagement Technology: From Undruggable to Druggable Targets in Cancer Therapeutics

“…The table below show a KRAS_G12C exchange assay and a KRAS_G12C pERK assay, where the symbols indicate IC 50 for † ≤ 100 nM, †† > 100 nM but ≤ 1 μM, ††† > 1 μM but ≤ 5 μM, and †††† > 5 μM but ≤ 10 μM. …”

Long-Awaited Small-Molecule Drug Candidate for Drugging the Next Undruggable KRASG12D Mutant in Cancer Therapy

“…The table below shows cell growth inhibition of IC 50 on KRAS G12D mutant, wherein I means ≤500 nM, II means 500–5000 nM, and III means >5000 nM. …”