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Review
. 2024 Oct 12;16(20):3455.
doi: 10.3390/cancers16203455.

KRAS, a New Target for Precision Medicine in Colorectal Cancer?

Alice Boilève  1   2   3 , Cristina Smolenschi  1   4 , Aurélien Lambert  5 , Valérie Boige  1 , Matthieu Delaye  1 , Géraldine M Camilleri  1 , Anthony Tarabay  1 , Marine Valéry  1 , Alina Fuerea  1 , Thomas Pudlarz  1 , Jacques R R Mathieu  2   3 , Fanny Jaulin  2   3 , Antoine Hollebecque  1   4 , Michel Ducreux  1   2
Affiliations
Review

KRAS, a New Target for Precision Medicine in Colorectal Cancer?

Alice Boilève et al. Cancers (Basel). .

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS mutations are prevalent in CRC and are associated with poor prognosis. However, breakthroughs in drug development have led to the emergence of KRAS inhibitors as promising treatment options. This review discusses various classes of KRAS inhibitors, including covalent and non-covalent inhibitors, as well as combination therapies aimed at enhancing efficacy and overcoming resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise for improving patient outcomes in the future.

Keywords: KRAS; colorectal cancer; molecular profile; precision medicine; targeted therapies.

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Conflict of interest statement

Author A.B. received congress invitations of Merck, Ipsen, Servier. The remaining 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 in the context of this review.

Figures

Figure 1
Figure 1
KRAS pathway (created with biorender).
Figure 2
Figure 2
KRAS mutations prevalence in solid tumors and CRC. (A) Percentage of KRAS alterations (tumors with prevalence > 10%), according to the GENIE cohort v13.0-public (red: colorectum) [4]. (B) KRAS mutation prevalence in CRC (from [1]).
Figure 3
Figure 3
Mechanisms of bypassing KRAS inhibitors through the activation of wild-type (WT) forms of RAS (NRAS and HRAS) [29,31] (biorender).
Figure 4
Figure 4
Therapeutic approaches to target KRAS.
See this image and copyright information in PMC

References

    1. Hofmann M.H., Gerlach D., Misale S., Petronczki M., Kraut N. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer Discov. 2022;12:924–937. doi: 10.1158/2159-8290.CD-21-1331. - DOI - PMC - PubMed
    1. Prior I.A., Lewis P.D., Mattos C. A Comprehensive Survey of Ras Mutations in Cancer. Cancer Res. 2012;72:2457–2467. doi: 10.1158/0008-5472.CAN-11-2612. - DOI - PMC - PubMed
    1. Cerami E., Gao J., Dogrusoz U., Gross B.E., Sumer S.O., Aksoy B.A., Jacobsen A., Byrne C.J., Heuer M.L., Larsson E., et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discov. 2012;2:401–404. doi: 10.1158/2159-8290.CD-12-0095. - DOI - PMC - PubMed
    1. André F., Arnedos M., Baras A.S., Baselga J., Zhang H., AACR Project GENIE Consortium AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017;7:818–831. doi: 10.1158/2159-8290.CD-17-0151. - DOI - PMC - PubMed
    1. Väyrynen V., Wirta E.-V., Seppälä T., Sihvo E., Mecklin J.-P., Vasala K., Kellokumpu I. Incidence and Management of Patients with Colorectal Cancer and Synchronous and Metachronous Colorectal Metastases: A Population-Based Study. BJS Open. 2020;4:685–692. doi: 10.1002/bjs5.50299. - DOI - PMC - PubMed

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