Targeting KRAS mutant lung cancer: light at the end of the tunnel

Abstract

For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRAS^G12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.

Keywords: KRASG12C inhibitors; RAF1; RAS signaling; genetically engineered mouse tumor models; lung adenocarcinoma; tumor resistance.

Fig. 1

Frequency of KRAS mutations in human LUAD. Data were obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC) database of the Sanger Institute v94 (released May 28, 2021).

Fig. 2

Potential strategies to target KRAS in LUAD. (A) Schematic representation of upstream (tyrosine kinase receptors, RTK, tyrosine phosphatase SHP2, and the guanine nucleotide exchange factor SOS) and downstream (RAF, MEK and ERK kinase families and the cell cycle kinase CDK4) KRAS effectors. Those strategies that interfere with KRAS signaling at different levels are shown as white boxes. White boxes with crossed red lines indicate pharmacological strategies that, so far, have not been approved by the FDA for the treatment of KRAS mutant cancers (see reviews [3, 77, 98]). (B) Inhibition of KRAS signaling by DDR1 and NOTCH inhibitors [115].

Fig. 3

Potential strategies to target RAF1 in KRAS‐driven LUAD. White boxes indicate conceivable therapeutic options and grey boxes the consequences on tumor growth. (A) RAF1 ablation or its degradation has no effect of MAPK signaling or normal homeostasis. However, it causes regression of LUAD via kinase‐independent functions. (B) RAF1 blocks apoptosis by activating ASK1 and MST2. Hypothetical RAF1/ASK1 or RAF1/MST2 inhibitors are predicted to liberate ASK1 and MST2 from the inhibitory effect of RAF1 kinase–independent activity to induce apoptosis.