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

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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

DOI 10.1158/2159-8290.cd-13-0063PMC PMC3864542

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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.
ORCID: Klempner, Samuel J.
Cantley, Lewis C.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2013-12-01
Volume: 3
Issue: 12
Pages: 1345-1354
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-13-0063
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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What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway

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