Cited by 148PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerAdvanced Breast Cancer Therapies

What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway

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Klempner, Samuel J., Myers, Andrea P., Cantley, Lewis C.·2013·Cancer Discovery

Abstract

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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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
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
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 › Pulmonary and Respiratory Medicine › 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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