Xinchao Zhao,* Yawen Zheng,* Yufeng Wang, Mingyan Zhang, Zhilin Dong, Yanan Liu, Meili Sun

Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Meili Sun, Email smli1980@163.com

Abstract: In non-small cell lung cancer (NSCLC), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in up to 30% of all cases, with the most prevalent mutations occurring in codons 12 and 13. The development of KRAS-targeted drugs like sotorasib and adagrasib has generated significant excitement in the clinical arena, offering new therapeutic options. Their potential for combination with other treatments broadens the scope for clinical exploration. Acquired resistance to KRAS exon 2 p.G12C inhibitors is a significant challenge, with several reported mechanisms. In this scenario, combination therapy strategies that include targeting Src Homology Region 2 Domain-Containing Phosphatase-2 (SHP2), Son of Sevenless Homolog 1 (SOS1), or downstream effectors of KRAS exon 2 p.G12C are showing promise in overcoming such resistance. However, the efficacy of immune checkpoint inhibitors in this context still requires comprehensive evaluation. The response to anti-Programmed Cell Death Protein 1/Programmed Cell Death Protein 1 Ligand (anti-PD-1/PD-L1) drugs in NSCLC may be significantly influenced by co-occurring mutations, underscoring the need for a personalized approach to treatment based on the specific genetic profile of each tumor.

Keywords: targeted therapies, sotorasib, adagrasib, resistance