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Review
. 2022 Nov 16:11:2022-7-4.
doi: 10.7573/dic.2022-7-4. eCollection 2022.

How to manage KRAS G12C-mutated advanced non-small-cell lung cancer

Biagio Ricciuti  1 , Alessia Mira  2 , Elisa Andrini  3   4 , Pietro Scaparone  2 , Sandra Vietti Michelina  2 , Federica Pecci  1 , Luca Cantini  5 , Andrea De Giglio  3   4 , Giuseppe Lamberti  3   4 , Chiara Ambrogio  2 , Giulio Metro  6
Affiliations
Review

How to manage KRAS G12C-mutated advanced non-small-cell lung cancer

Biagio Ricciuti et al. Drugs Context. .

Abstract

Constitutive KRAS signalling drives tumorigenesis across several cancer types. In non-small-cell lung cancer (NSCLC) activating KRAS mutations occur in ~30% of cases, and the glycine to cysteine substitution at codon 12 (G12C) is the most common KRAS alteration. Although KRAS mutations have been considered undruggable for over 40 years, the recent discovery of allelic-specific KRAS inhibitors has paved the way to personalized cancer medicine for patients with tumours harbouring these mutations. Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC.

Keywords: G12C; KRAS; NSCLC; immunotherapy; sotorasib.

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Conflict of interest statement

Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/10/dic.2022-7-4-COI.pdf

Figures

Figure 1
Figure 1
Signalling pathways in wild-type and mutant KRAS cells. (A) KRAS plays a crucial role in signalling through the MAPK pathway, the PI3K–Akt–mTOR pathway and the NF-kB pathway. (B) Mutations in KRAS result in enhanced GTP-loading, causing aberrant activation of the MAPK pathway.
Figure 2
Figure 2
(A) KRAS GTPase cycle. GTP binding is induced by guanine nucleotide-exchange factors (GEFs) and GTP hydrolysis is catalysed by GTPase-activating proteins (GAPs) to cycle KRAS from the active form to the inactive form. (B) Sotorasib (red) binding GDP (blu)-KRAS G12C in Switch II pocket. (C) GDP (blu)-KRAS G12C binding with MRTX-849 (red) in Switch II pocket. (Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.)
Figure 3
Figure 3
Proposed therapeutic algorithm for patients with KRAS G12C-mutant non-small-cell lung cancer.
See this image and copyright information in PMC

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