GSK-2636771

Circumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1-a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide-inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, αCT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that αCT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit β (PIK3CB, also called PI3Kβ or p110β), suggesting that Cx43 activates PIK3CB/p110β independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110β, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110β-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110β together is an effective therapeutic approach for overcoming chemoresistance.

In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR) targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory phosphatase and tensin homolog (PTEN) activates phosphoinositide 3-kinase (PI3K)/AKT signaling and contributes to resistance to androgen-deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.

In this Phase I study (NCT02215096), patients with PTEN-deficient mCRPC, who progressed on prior enzalutamide, received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100 mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended Phase II dose (RP2D), and assess the 12-week non-progressive disease (PD) rate.

Overall, 37 patients were enrolled; 36 received {greater than or equal to}1 dose of GSK2636771 (200 mg: n=22, 300 mg: n=12; 400 mg: n=2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n=1; 300 mg: n=2, 400 mg: n=2). No new or unexpected adverse events nor evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% CI: 28.2-71.8%, n=22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. 4/34 (12%) patients had prostate-specific antigen reduction of {greater than or equal to}50%.

Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.