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REVIEW ARTICLE

The role of PIK3CA in advanced and metastatic colorectal cancer and the therapeutic potential and efficacy of PIK3CA inhibitors

Humza Mallick1 ,  Marcus Yoakam1 ,  Samir Dalia2*
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1 Department of Medical Education, College of Osteopathic Medicine, Kansas City University, Joplin, Missouri, United States of America
2 Department of Medical Oncology, Mercy Hospital, Joplin, Missouri, United States of America
Tumor Discovery, 025300071 https://doi.org/10.36922/TD025300071
Received: 24 July 2025 | Revised: 16 September 2025 | Accepted: 16 October 2025 | Published online: 31 October 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Colorectal cancer (CRC) is one of the most prevalent malignancies globally and is the leading cause of cancer mortality worldwide. Advanced and metastatic CRC is associated with poor prognosis due to high rates of metastases and resistance to standard therapies. With the advent of next-generation sequencing, there has been increased interest in molecularly targeted treatments. One such molecular target is the PIK3CA gene, a key component of the phosphatidylinositol 3-kinase (PI3K) pathway, which has been linked to promoting tumor survival and proliferation in cancer cell populations. PIK3CA mutations are detected in approximately 10–20% of CRC cases. The presence of these mutations has both prognostic and predictive implications, particularly in regards to providing resistance to standard-of-care CRC therapies. Targeting PIK3CA with selective PI3K inhibitors has shown modest results: in the Copanlisib NCI-MATCH trial, objective responses were observed in 16% of patients with PIK3CA-mutant tumors, although CRC patients experienced only disease stabilization without tumor shrinkage. Similarly, in the Taselisib phase II basket study, median progression-free survival was 3.1 months with no complete or partial responses in CRC cohorts. These findings highlight the limited therapeutic efficacy of PI3K inhibitors in CRC, driven by factors including toxicity, adaptive resistance, pathway crosstalk, and tumor co-mutation profiles. The current research is focused on optimizing combination strategies, refining patient selection through biomarkers, targeting specific isoforms within the PI3K pathway, and overcoming resistance mechanisms to unlock the full therapeutic potential of PI3K-targeted therapies for advanced and metastatic CRC.

Keywords
PIK3CA
Colorectal cancer
PI3K inhibitors
Targeted therapy
Mutations
Antineoplastic agents
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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