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Review
. 2024 Jan 4:29:1611580.
doi: 10.3389/pore.2023.1611580. eCollection 2023.

KRASG12C mutant lung adenocarcinoma: unique biology, novel therapies and new challenges

Judit Moldvay  1   2 , József Tímár  3
Affiliations
Review

KRASG12C mutant lung adenocarcinoma: unique biology, novel therapies and new challenges

Judit Moldvay et al. Pathol Oncol Res. .

Abstract

KRAS mutant lung cancer is the most prevalent molecular subclass of adenocarcinoma (LUAD), which is a heterogenous group depending on the mutation-type which affects not only the function of the oncogene but affects the biological behavior of the cancer as well. Furthermore, KRAS mutation affects radiation sensitivity but leads also to bevacizumab and bisphosphonate resistance as well. It was highly significant that allele specific irreversible inhibitors have been developed for the smoking associated G12C mutant KRAS (sotorasib and adagrasib). Based on trial data both sotorasib and adagrasib obtained conditional approval by FDA for the treatment of previously treated advanced LUAD. Similar to other target therapies, clinical administration of KRASG12C inhibitors (sotorasib and adagrasib) resulted in acquired resistance due to various genetic changes not only in KRAS but in other oncogenes as well. Recent clinical studies are aiming to increase the efficacy of G12C inhibitors by novel combination strategies.

Keywords: G12C mutation; KRAS; adagrasib; lung adenocarcinoma; sotorasib.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Molecular classification of lung adenocarcinoma.
FIGURE 2
FIGURE 2
Connection between smoking history and KRAS mutant types in lung adenocarcinoma [10].
FIGURE 3
FIGURE 3
Effect of G12C inhibitors on the function of mutant KRAS protein [11]. (A) Function of the G12C mutated KRAS protein. (B) Function of the G12C mutated KRAS protein bound to inhibitors. Ad, adagrasib; GAP, GTP-ase activating protein; GEF, guanin nucleotide exchange factor; GFR, growth factor receptor; So, sotorasib.
See this image and copyright information in PMC

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