Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead

Abstract

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRas^G12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRas^G12C have shown promising efficacy against cancers harboring KRAS^G12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRAS^G12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRas^G12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^G12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRas^G12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

Keywords: Biomarkers; Covalent KRasG12Cinhibitors; Drug resistance; Human cancers; KRASG12Cmutation.

Figure 1

The Ras signaling pathway. Activated Ras by upstream RTKs or by gain-of-function mutation possesses high affinity with GTP and further activates multiple downstream signaling pathways, including Raf/MEK, PI3K/Akt and Ral/GEF cascades, which regulate important processes such as cell growth, differentiation, apoptosis, invasion, and metastasis.

Figure 2

Frequency of KRAS alterations in human cancers. The 10 cancer types with most frequent KRAS alterations are presented. Data are derived from 13,602 samples in “PanCancer Studies” analyzed by cBioPortal (www.cbioportal.org/, accessed in July 2020).

Figure 3

The mechanism of the activation of KRas and KRas^G12C covalent inhibitors. KRas switches between active and inactive state by binding to GTP and GDP, respectively. GEFs facilitate the release of GDP, while GAPs strengthen the relatively poor intrinsic GTP enzyme activity of KRas. KRas^G12C covalent inhibitors are mainly considered to lock KRas^G12C in the inactive KRas-GDP state.

Figure 4

A chronicle of discovery and development of KRas^G12C covalent inhibitors.