Exploring the Pathway: The PI3K Pathway Fact Sheet

Exploring the Pathway: The PI3K Pathway Fact Sheet

The phosphoinositide 3-kinase (PI3K) signaling pathway regulates many cellular processes, such as cell growth, metabolism, survival, and proliferation, and it plays a critical role in human malignancy. The PI3K pathway is one of the most frequently altered pathways in human cancers. Not surprisingly, tremendous time and resources have been committed to the clinical development of therapeutic agents targeting nearly every aspect of this pathway.

What Is the PI3K Pathway?

PI3Ks are lipid kinases that phosphorylate the 3’-OH group of phosphoinositides. There are three classes of PI3Ks with distinct structures, cellular distributions, mechanisms of action, and substrate preferences, and these are further divided into subclasses and isoforms. The phosphorlylating activity of class 1A PI3K leads to activation of protein kinase B (Akt), and one downstream effector of Akt that is particularly relevant to cancer is the kinase mTOR. Because each of these kinases (PI3K, Akt, and mTOR) regulate critical signaling networks for cancer, there is ample rationale for their emergence as therapeutic targets for drug development.

Therapeutic Targeting of the PI3K Pathway

The PI3K pathway is perhaps one of the most therapeutically investigated targets in cancer. Agents targeting this pathway that have been clinically investigated include:

  • Rapalogs were the first agents clinically investigated. Temsirolimus and everolimus demonstrated single-agent clinical activity in renal cell carcinoma, mantle cell lymphoma, and some neuroendocrine tumors. However, preclinical investigation suggested the presence of a feedback loop that undermines the effects of these agents.
  • Pan-isoform PI3K inhibitors are direct inhibitors of p110 kinase activity that act as Akt mimetics, binding competitively to the p110 ATP-binding pocket. Several of these drugs have been investigated in phase I and phase II trials in multiple disease types and have been relatively well tolerated. Toxicities have included hyperglycemia (likely a result of the role of PI3K in insulin signaling), skin toxicity, and gastrointestinal side effects. The pan-isoform PI3K inhibitor furthest along in clinical development is BKM120, which is currently being investigated in a phase III placebo-controlled clinical trial in patients with hormone-positive HER2-negative breast cancer who are postmenopausal (NCT01610284).
  • A class of dual PI3K/mTOR inhibitors has been developed with the hope that these may have broader activity in cancers in which PI3K/Akt is not the primary driver of mTOR activity and that they might prevent the aforementioned feedback activation of PI3K. Early-phase studies suggest that the toxicities of this class of pan-isoform inhibitors of PI3K and mTOR are similar to those of pan-isoform PI3K inhibitors and that they do not display some of the toxicities of the rapalogs. A few of these agents have reached phase II clinical trials in a variety of diseases; in general, although some objective tumor responses have been observed, the activity of these agents has been modest. No clinical trial with a pan-isoform PI3K inhibitor or a dual PI3K/mTOR inhibitor has reported robust clinical activity, even in tumors with known genetic alterations.
  • Because of the modest efficacy of earlier-generation PI3K inhibitors, the greatest enthusiasm remains for isoform-specific PI3K inhibitors. The primary theoretical advantage of isoform-specific inhibitors is that they may have more focused toxicities compared with pan-isoform inhibitors, allowing them to be tolerated at higher doses that might result in more complete and reliable inhibition of kinase activity. There has been great interest in the activity of PI3K-alpha inhibitors in cancers with PIK3CA mutations, PI3K-beta inhibitors in tumors with PTEN loss, and PI3K-delta inhibitors in hematologic malignancies.

A PI3K-delta inhibitor, idelalisib, received U.S. Food and Drug Administration approval last year for use in combination with rituximab for patients with relapsed chronic lymphocytic leukemia for whom rituximab alone would be considered appropriate therapy and as monotherapy for patients with relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma who received at least two prior systemic therapies.

  • Also advancing through clinical trials are Akt inhibitors, to date all of which are pan-isoform inhibitors of Akt. Toxicities observed have been similar to those of pan-isoform PI3K inhibitors, and clinical activity has been modest. It is thought that patient selection might be an issue, and that these drugs might be best directed to cancers with Akt alterations and PTEN loss.

Future Challenges

For most of the agents described above, phase I clinical trials have been completed and toxicity profiles established. Although the agents have been well tolerated, their early-phase studies have shown relatively modest single-agent clinical activity. As these drugs move deeper into clinical assessment, there will be challenges to enhance their therapeutic index. Continued optimism is driven by the promise of the further development of isoform-specific PI3K inhibitors, identification of more predictive biomarkers of response in conjunction with enhanced knowledge of the biology of specific genetic alterations, and the promise of combination of these drugs with other molecularly targeted agents.

This Fact Sheet was condensed and adapted from an editorial by Daniel Cho, MD, published previously in the ASCO Daily News entitled “Exploring the Pathway: Despite Lukewarm Clinical Benefit of PI3K Inhibitors, Optimism Remains Regarding Biomarkers and Combination Therapy”.