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Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment

Long, Szu-Aun, Amparo, Amber M., Goodhart, Grace, Ahmad, Syed A., Waters, Andrew M.·2024·Frontiers in Oncology
DOI 10.3389/fonc.2024.1402128PMC PMC11116577
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Abstract

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world’s deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms.

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Metadata

Authors
Long, S.-A., Amparo, A. M., Goodhart, G., Ahmad, S. A., & Waters, A. M.
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2024-05-10
Volume
14
ISSN
2234-943X
DOI
10.3389/fonc.2024.1402128
PMC
PMC11116577
Cited by
31
References
37
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Institutes of Health

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