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CLINICAL OUTLOOK

KRAS inhibitors, approved

Nature Cancer volume 2, pages 1254–1256 (2021)Cite this article

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The rapid progression of KRAS(G12C) inhibitors from preclinical characterization to the clinic has radically changed the perception of the KRAS oncogene as an undruggable target. Here we discuss ongoing and future possibilities for developing therapies using these inhibitors in clinical settings.

KRAS guanosine triphosphate hydrolase (GTPase) regulates downstream signaling through the engagement of effectors with high affinity toward its active, GTP-bound conformation. GTP hydrolysis is catalyzed by three key domains within the KRAS protein: the p-loop (residues 10–17), switch I (residues 30–38) and switch II (residues 60–76). KRAS activation is tightly regulated by the guanine nucleotide exchange factor SOS1, which promotes the exchange of GDP for GTP to activate the inactive GDP-bound KRAS. Downstream effectors, including RAF kinases, PI3K, RALA and RALB among others, contain KRAS-binding domains. Single amino acid substitutions in the KRAS GTPase p-loop domain, such as those involving the G12 (D/C/V/R/A/S) or G13 (D/C/V) residues, result in the constitutive activation of the KRAS oncoprotein by hindering its capacity to hydrolyze GTP1.

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Fig. 1: Intrinsic and acquired mechanisms of resistance to targeted KRAS(G12C) inhibitors in NSCLC.

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Acknowledgements

R.R. reports funding from the Spanish Association Against Cancer (AECC; grant PROYE18012ROSE), a European Union Horizon 2020 research and innovation program, Marie Sklodowska-Curie grant agreement ELBA N 765492 and the Talent-UAB grant to support recruitment and retention of research talent at the Autonomous University of Barcelona.

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  1. Catalan Institute of Oncology, Badalona, Spain

    Rafael Rosell

  2. Oncology Institute Dr Rosell, IOR, Barcelona, Spain

    Rafael Rosell & Andrés Aguilar

  3. Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain

    Rafael Rosell, Carlos Pedraz & Imane Chaib

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  1. Rafael Rosell
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Correspondence to Rafael Rosell.

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Rosell, R., Aguilar, A., Pedraz, C. et al. KRAS inhibitors, approved. Nat Cancer 2, 1254–1256 (2021). https://doi.org/10.1038/s43018-021-00289-3

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