Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors

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-specifi c 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 isoformspecifi c PI3K inhibitors, particularly in combination with other agents, may be valuable in treating appropriately selected patients with PI3K-dependent tumors.