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Mini Review

Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors

Ariella B. Hanker, Virginia Kaklamani and Carlos L. Arteaga
Ariella B. Hanker
Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Virginia Kaklamani
The University of Texas Health Science Center, San Antonio, Texas.
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Carlos L. Arteaga
Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
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  • For correspondence: carlos.arteaga@utsouthwestern.edu
DOI: 10.1158/2159-8290.CD-18-1175 Published April 2019
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Abstract

The PI3K pathway is mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival, making it a rational therapeutic target. Until recently, however, results from clinical trials with PI3K inhibitors in solid tumors have been largely disappointing. Here, we describe several factors that have limited the success of these agents, including the weak driver oncogenic activity of mutant PI3K, suboptimal patient selection in trials, drug-related toxicities, feedback upregulation of compensatory mechanisms when PI3K is blocked, increased insulin production upon PI3Kα inhibition, lack of mutant-specific inhibitors, and a relative scarcity of studies using combinations with PI3K antagonists. We also suggest strategies to improve the impact of these agents in solid tumors. Despite these challenges, we are optimistic that isoform-specific PI3K inhibitors, particularly in combination with other agents, may be valuable in treating appropriately selected patients with PI3K-dependent tumors.

Significance: Despite the modest clinical activity of PI3K inhibitors in solid tumors, there is an increasing understanding of the factors that may have limited their success. Strategies to ameliorate drug-related toxicities, use of rational combinations with PI3K antagonists, development of mutant-selective PI3K inhibitors, and better patient selection should improve the success of these targeted agents against solid tumors.

  • Received October 7, 2018.
  • Revision received January 4, 2019.
  • Accepted January 16, 2019.
  • Published first March 13, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (4)
April 2019
Volume 9, Issue 4
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Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors
Ariella B. Hanker, Virginia Kaklamani and Carlos L. Arteaga
Cancer Discov April 1 2019 (9) (4) 482-491; DOI: 10.1158/2159-8290.CD-18-1175

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Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors
Ariella B. Hanker, Virginia Kaklamani and Carlos L. Arteaga
Cancer Discov April 1 2019 (9) (4) 482-491; DOI: 10.1158/2159-8290.CD-18-1175
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  • Article
    • Abstract
    • Introduction
    • PIK3CA Mutations are Weak Oncogenes
    • Suboptimal Patient Selection in Clinical Trials
    • Drug-Related Toxicity Limits Sustained Target Inhibition
    • Feedback Upregulation of Compensatory Mechanisms
    • Increase in Insulin Production Upon Inhibition of PI3K
    • Lack of Mutant PIK3CA-Specific Inhibitors
    • Other Mechanisms of Resistance
    • Recent Advances in Targeting the PI3K/AKT Pathway in Solid Tumors
    • Conclusions
    • Disclosure of Potential Conflicts of Interest
    • References
  • Figures & Data
  • Info & Metrics
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