Current therapy of KRAS-mutant lung cancer

Abstract

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.

Keywords: KRAS mutation; Lung cancer; Predictive factor; Prognostic factor; Targeted therapy.

Fig. 1

KRAS mutational subtypes and smoking history in lung adenocarcinoma (LADC) [12]. In current (a) and former (b) smokers, KRAS G12C is the most common mutation, while KRAS G12D is the most frequent mutation among never smokers (c). Overall (d), the most frequently diagnosed KRAS mutational subtype in LADC patients is KRAS G12C, followed by KRAS G12V, KRAS G12D, and KRAS G12A

Fig. 2

A chronicle of KRAS mutation in lung cancer. Major biological discoveries and key clinical trials. During its more than 30-year history, our knowledge of KRAS mutation in lung cancer has progressed through a series of phases. Although the relationship between RAS genes and lung cancer was described in 1984, the first clinical trials investigating the efficacy of indirect KRAS inhibitors were carried out only in the early 2000s. Since then, large numbers of both direct and indirect KRAS inhibitors have been developed and tested. However, until recently, efforts to target the RAS family proteins were mostly ineffective in the clinics. At the same time, in the past years, a worldwide awakening of interest led to rapid translational progress and to the discovery of novel direct covalent KRAS G12C-inhibitors, some of which have been tested in clinical trials. The renewed enthusiasm and biological and clinical progress have changed the landscape of KRAS-mutated lung cancer and have led to the first serious discussions of whether RAS is indeed a druggable target. KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK, MAPK/ERK kinase; mTOR, mammalian target of rapamycin; MET, MET proto-oncogene; Hsp90, heat shock protein 90; CDK4/6, cyclin-dependent kinases 4/6; FAK, focal adhesion kinase; OS, overall survival