AUTHOR=Désage Anne-Laure , Léonce Camille , Swalduz Aurélie , Ortiz-Cuaran Sandra 

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

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.796832

DOI=10.3389/fonc.2022.796832

ISSN=2234-943X

ABSTRACT=<p>Although <italic>KRAS-</italic>activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit <italic>KRAS</italic> failed in the past decade. <italic>KRAS</italic> mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (<italic>i.e.</italic>, adagrasib, sotorasib) that target specifically <italic>KRAS G12C</italic> 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 <italic>KRAS G12C</italic> inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of <italic>KRAS G12C</italic> seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting <italic>KRAS G12C</italic> and promising approaches of combined therapy to overcome acquired resistance to <italic>KRAS G12C</italic> inhibitors.</p>