Challenges in the clinical development of PI3K inhibitors

Abstract

The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated signaling pathways in cancer and an important target for drug development. PI3K signaling plays a fundamental role in tumorigenesis, governing cell proliferation, survival, motility, and angiogenesis. Activation of the pathway is frequently observed in a variety of tumor types and can occur through several mechanisms. These mechanisms include (but are not limited to) upregulated signaling via the aberrant activation of receptors upstream of PI3K, amplification or gain-of-function mutations in the PIK3CA gene encoding the p110α catalytic subunit of PI3K, and inactivation of PTEN through mutation, deletion, or epigenetic silencing. PI3K pathway activation may occur as part of primary tumorigenesis, or as an adaptive response (via molecular alterations or increased phosphorylation of pathway components) that may lead to resistance to anticancer therapies. A range of PI3K inhibitors are being investigated for the treatment of different types of cancer; broad clinical development plans require a flexible yet well-structured approach to clinical trial design.

F-box protein interactions with the hallmark pathways in cancer

“…Mitogenic and pro-survival receptor signalling pathways are often deregulated in cancer, including but not limited to growth factor receptor pathways controlled by EGFR, FGFR, and ERBB2, as well as WNT, Notch, and Sonic Hedgehog cytokine signalling pathways. Cross-talk among receptor signalling pathways display a robustness A c c e p t e d M a n u s c r i p t 9 and redundancy which is problematic for cancer therapeutics (78)(79)(80)(81)(82)(83). This is evidenced by the fact that pharmacological inhibitors to specific receptors are often bypassed by increasing signalling via a different receptor.…”

Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy

“…PI3K consists of a heterodimer of an 85kDa regulatory and a 110kDa catalytic subunits including PIK3CA, PIK3CB, or PIK3CD that can be activated by RTKs, through phosphorylation of phosphatidylinositol-4,5-biphosphate phosphates to phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits phosphoinositide dependent kinase (PDK1) at cell membrane to induce downstream effectors 19, 20 . The catalytic activity of the PI3K, which is negatively regulated by PTEN, lead to up-regulation of p-AKT and the stimulation of critical cellular functions including cell proliferation, migration, survival and cell differentiation 21, 22 .…”

Targeting Therapeutic Liabilities Engendered by PIK3R1 Mutations for Cancer Treatment

“…Encouragingly, GS-1101 (p110δ-specific, previously known as CAL-101) a p110δ-specific inhibitor has shown remarkable success in the clinic for the treatment of hematopoietic malignancies that express relatively high levels of p110δ [29]. In addition, an array of second generation and more potent agents targeting the PI3K pathway are in development or early clinical trials [30,31]. Blocking upstream signaling from RTKs provide an indirect approach to inhibiting the PI3K pathway.…”