Abstract S6-04: The PI3K inhibitor, taselisib, has enhanced potency in PIK3CA mutant models through a unique mechanism of action

Abstract

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutational activation of the PIK3CA gene. The dysregulation of this pathway has been implicated in tumor cell growth and survival, thus PI3K is a promising therapeutic target with multiple inhibitors in clinical trials. Taselisib (GDC-0032), a novel, oral, selective inhibitor of p110alpha, sparing inhibition of p110beta, is more potent against cancer cells bearing mutations in the PIK3CA gene than those with wildtype PIK3CA. The mechanism leading to this enhanced mutant selectivity is revealed in these preclinical studies. Uniquely among PI3K inhibitors, taselisib has a gain of potency in PIK3CA mutant SW48 isogenic cells compared to wildtype SW48 parental cells. Pathway inhibition and increased apoptosis are associated with the enhanced activity observed in PIK3CA mutant cells. In PIK3CA mutant cell culture-derived and patient-derived xenograft (PDX) models taselisib induces tumor regressions. In comparison to other clinical-stage PI3K inhibitors, taselisib confers superior anti-tumor activity in PIK3CA mutant xenografts when treated at a Maximum Tolerated Dose (MTD) in vivo. We have discovered that taselisib has a dual mechanism of action, both blocking kinase signaling and inducing down-regulation of the mutant p110alpha protein level in a dose-dependent and time-dependent manner. Taselisib treatment leads to the specific degradation of mutant p110alpha without significant change in wildtype p110alpha protein in cultured cells and in mutant xenograft models including PDX. Other clinical PI3K inhibitors, including PI3Kalpha selective and pan-PI3K inhibitors are unable to induce degradation of mutant p110 alpha. The taselisib-induced degradation of mutant p110a protein is ubiquitin-mediated and proteasome-dependent. These unique mechanistic effects of taselisib are most pronounced when comparing signaling suppression and p110a protein levels at 24 hours vs. 1 hour of drug exposure in PIK3CA mutant cell lines. This discovery indicates that PI3K inhibitors which trigger degradation of mutant p110a protein can more effectively suppress the signaling pathway in response to feedback, and may result in greater activity and improved therapeutic index. Citation Format: Friedman LS, Edgar KA, Song K, Schmidt S, Kirkpatrick DS, Phu L, Nannini MA, Hong R, Cheng E, Crocker L, Young A, Sampath D. The PI3K inhibitor, taselisib, has enhanced potency in PIK3CA mutant models through a unique mechanism of action [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-04.

Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

“…Taselisib has increased potency against the mutant version of the PI3K alpha isoform, as demonstrated in chemical assays as well as in cancer cell lines (6). A higher therapeutic window due to greater selectivity for PIK3CA mutant isoforms has been shown in extensive laboratory studies (21) and is also suggested by the fact that partial responses were only observed in patients with PIK3CA-mutant tumors. The other indirect evidence for an enhanced therapeutic window is that at the chosen recommended dose, patients were able to stay on the study agent for prolonged periods of time.…”

The PI3K Pathway in Human Disease

“…Early clinical trials of the isoform-selective inhibitors, alpelisib and taselisib, in breast cancer have produced results consistent with a previous meta-analysis of clinical trials of PI3K pathway inhibitors in patients with diverse cancers, revealing that patients with H1047R mutations had higher response rates than those with other PIK3CA mutations, or no mutations in this gene (Janku et al, 2013; Mayer et al, 2017). The p110β-sparing inhibitor, taselisib, (Table S1) was reported to induce degradation of mutant p110α (Friedman et al, 2017). It is conceivable that distinct activating mutations in p110α might confer differential susceptibilities drug-induced degradation; if this proves to be the case, perhaps drug-induced turnover of the p110α H1047R mutant underlies the increased taselisib sensitivity of tumors expressing this particular p110α oncoprotein.…”

Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors

“…Tumor PIK3CA H1047R in cancer cells in culture and patient-derived xenografts (PDX) without significant change in WT p110α (62). It spares p110β but also inhibits p110γ and p110δ.…”