Targeting Oncogenic KRAS in Non-Small-Cell Lung Cancer

Abstract

Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance.

Keywords: combination therapy; covalent KRAS G12C inhibitor; drug resistance; non-small-cell lung cancer; v-Ki-ras2 Kirsten rat sarcoma viral oncogene.

Figure 1

Frequencies of KRAS mutation subtypes in NSCLC, colorectal cancer and pancreatic cancer. The pie charts were made based on data from the AACR Project GENIE: Powering Precision Medicine through an International Consortium (GENIE Cohort v10.0-public; Ref. [22]).

Figure 2

Schematic of Ras signaling pathways and the mechanisms of resistance to covalent KRAS G12C inhibitors in NSCLC. Amplification of the KRAS G12C allele, mutations in KRAS, NRAS, BRAF, MEK1 and PI3KCA, and MET amplification (marked in red) have been observed in patients with acquired resistance to sotorasib or adagrasib [16,17]. T symbol in red: therapeutic targets combined with KRAS G12 inhibitors in clinical trials (Table 1). RTK: receptor tyrosine kinase; Mut: mutation; Amp: amplification.