PI3Kinase Inhibition in Hormone Receptor-Positive Breast Cancer.

Ajay Dhakal,Shipra Gandhi,Luna Acharya,Carla Falkson,Ruth O’Regan

doi:10.3390/ijms222111878

Abstract

Derangement of the phosphatidylinositol-3 kinase (PI3K) pathway is implicated in several subtypes of breast cancers. Mutation or upregulation of PI3K enhances cancer cells’ survival, proliferation, and ability to metastasize, making it an attractive molecular target for systemic therapy. PI3K has four isoforms, and several drugs targeting individual isoforms or pan-PI3K have been or are currently being investigated in clinical trials. However, the search for an effective PI3K inhibitor with a robust therapeutic effect and reasonable safety profile for breast cancer treatment remains elusive. This review focuses on the recently completed and ongoing clinical trials involving PI3K inhibitors as mono- or combination therapy in breast cancer. We review the salient findings of clinical trials, the therapeutic efficacy of PI3K inhibitors, and reported adverse effects leading to treatment discontinuation. Lastly, we discuss the challenges and potential opportunities associated with adopting PI3K inhibitors in the clinic.

Highlights

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Following the receptor tyrosine kinase or a G protein receptor coupled activation, class I phosphatidylinositol-3 kinase (PI3K) are recruited to the cell membrane, p85 inhibition is relieved, and p110 phosphorylates phosphatidylinositides
Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 (16%) of 570 patients in the placebo group. This trial showed that PI3K pathway inhibition was effective in combination with endocrine therapy in advanced HR+ metastatic breast cancer (MBC), but more selective

Summary

Role and Discovery of PI3Kinase in Cancer

Phosphatidylinositol 3 kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 30 -hydroxyl group of lipids (PIP2 ) to Phosphatidylinositol 4,5trisphosphate (PIP3 ), and translate extracellular signals into cellular growth, proliferation, survival, cytoskeletal reorganization, membrane trafficking, and metabolism [1,2,3,4]. Following the receptor tyrosine kinase or a G protein receptor coupled activation, class I PI3Ks are recruited to the cell membrane, p85 inhibition is relieved, and p110 phosphorylates phosphatidylinositides. The common mechanisms leading to aberrant PI3K signaling include somatic loss of Phosphatase and tensin homolog (PTEN) via genetic or epigenetic alterations, activation of receptor tyrosine kinases, or alteration in various isoforms of PI3K [1,6,7]. There is very little evidence suggesting any oncogenic role of alterations in class III isoforms in cancer types. Upregulation of receptor tyrosine kinases, oncogenic RAS mutations, or activating p110α mutations increase phosphatidylinositide (3–5) triphosphate production through p110α. Even in the absence of other oncogenic mutations, loss of pTEN function can increase phosphatidylinositide (3–5) triphosphate production by p110β activity. An increase in phosphatidylinositide (3–5) triphosphate causes activation of downstream Akt/mTOR pathway leading to cell growth, proliferation, and angiogenesis

PI3K in Breast Cancer

Alpelisib

Utility and Limitation of Current Alpelisib Data

Opportunity and Challenges of Adopting PI3K Inhibitors in Clinic

Findings

10. Conclusions