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What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway
Open accessAbstract
The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors. Significance: There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer. Cancer Discov; 3(12); 1345–54. ©2013 AACR.
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“Even when marker-based predictions can be made, they do not guarantee patient response, as many are the result of correlations from population-based studies4, 5.”
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Metadata
- Authors
- Klempner, S. J., Myers, A. P., & Cantley, L. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Cantley, Lewis C.
- Venue
- Cancer Discovery
- Published
- 2013-12-01
- Volume
- 3
- Issue
- 12
- Pages
- 1345-1354
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3864542
- OpenAlex
- W2104167441
- Cited by
- 148
- References
- 110
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 2 · 2022: 11 · 2021: 19 · 2020: 12 · 2019: 7 · 2018: 11 · 2017: 18 · 2016: 23 · 2015: 18 · 2014: 12
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM041890, R01GM041890, R37GM041890)
- H2020 European Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Keywords
- phosphatidylinositol 3-kinase, PI3K inhibitors, drug resistance mechanisms, compensatory signaling, genomic changes, cancer therapy, targeted therapy, PI3K pathway mutations, clinical trial design
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Antineoplastic Agents, Humans, Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Translational Research, Biomedical, Molecular Targeted Therapy
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