Challenges for the Clinical Development of PI3K Inhibitors

Strategies to Improve Their Impact in Solid Tumors

Ariella B. Hanker, Virginia Kaklamani, Carlos L Arteaga

Research output: Contribution to journalReview article

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)482-491
Number of pages10
JournalCancer discovery
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2019

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Phosphatidylinositol 3-Kinases
Neoplasms
Drug-Related Side Effects and Adverse Reactions
Patient Selection
Cell Survival
Protein Isoforms
Up-Regulation
Cell Proliferation
Clinical Trials
Insulin

ASJC Scopus subject areas

  • Oncology

Cite this

Challenges for the Clinical Development of PI3K Inhibitors : Strategies to Improve Their Impact in Solid Tumors. / Hanker, Ariella B.; Kaklamani, Virginia; Arteaga, Carlos L.

In: Cancer discovery, Vol. 9, No. 4, 01.04.2019, p. 482-491.

Research output: Contribution to journalReview article

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