KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

Abstract

Lung cancer, the leading cause of cancer-related deaths worldwide, can be classified into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common histological type, accounting for 85% of all lung cancers. Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in NSCLC, are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted drugs. The latest published clinical trial data on new small-molecule KRAS G12C inhibitors, AMG510 and MRTX849, indicate that these molecules may potentially help treat KRAS-mutant NSCLC. Simultaneously, within the immuno-therapeutic process, immune efficacy has been observed in those patients who have KRAS mutations. In this article, the pathogenesis, treatment status, progress of immunotherapy, and targeted therapy of KRAS-mutant NSCLC are reviewed.

Keywords: AMG510; KRAS-mutant; MRTX849; NSCLC; immunotherapy; targeted therapy.

Figure 1

Inhibitors of Kirsten rat sarcoma viral oncogene homolog (KRAS) effector signalling. RAS protein acts as a binary molecular switch in a variety of signal transduction pathways. It is active when combined with GTP, but doesn’t have activity when combined with GDP. The GDP/GTP cycle is regulated by GEFs, which can promote the formation of active RAS - GTP and GAP stimulates GTP hydrolysis and forms inactive RAS - GDP. Normal RAS can be activated by upstream signalling factors, which in turn activates multiple downstream signalling pathways, including: MAPK, pathway; PI3k - AKT - mTOR, and pathway; RALGDS pathways. MAPK pathway, PI3K, pathway and JAK-STAT pathways promote the transcription of genes related to cell proliferation, metastasis, and drug resistance. PD -1 exists on the surface of activated T cells. When it is combined with PD-L1/2, it causes a series of immunosuppressive effects. Many Several methods have been developed to directly inhibit KRAS and inhibit KRAS downstream signalling pathways. Many new treatment strategies for KRAS inhibitors, KRAS downstream signalling pathway inhibitors, and ICIimmune checkpoint inhibitors are under investigation.