Combined CDK4/6 and PI3Kα Inhibition Is Synergistic and Immunogenic in Triple-Negative Breast Cancer.

Zhi Ling Teo,Sathana Dushyanthen,Wayne A Phillips,Phillip K Darcy,Grant A Mcarthur,Peter Savas,Franco Caramia,Chris P Mintoff,Sherene Loi,Stephen J Luen,Balaji Virassamy,Magnus Zethoven,Stephanie Versaci

doi:10.1158/0008-5472.can-17-2210

Abstract

New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wild-type TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell-cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T-cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell-cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC. Cancer Res; 77(22); 6340-52. ©2017 AACR.

Highlights

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is clinically characterized by its lack of expression of estrogen- and progesterone receptors (ER/PR) and HER2 [1]
We demonstrated that the interaction between BYL719 and LEE011 was synergistic in all six RB1-wild-type TNBC cell lines but was antagonistic in the RB1mutant cell line, MDA-MB-468 (Fig. 1A)
Consistent with this, we show in HCC1806 and MDA-MB-231 cell lines that BYL719 and LEE011 single-agent treatments resulted in reduction of AKT and retinoblastoma protein (RB) phosphorylation, respectively, compared with vehicle treatment, and both remained suppressed with combination treatment (Fig. 1C)

Summary

Introduction

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is clinically characterized by its lack of expression of estrogen- and progesterone receptors (ER/PR) and HER2 [1]. TNBC has the worst outcome of all breast cancer subtypes [1]. Cytotoxic chemotherapy is the mainstay of current treatment for TNBC patients. These regimens can prove effective for a subgroup of TNBC patients, in general, once relapsed, remissions are brief and are frequently followed by rapid disease progression and death. The existence of a tumor immune infiltrate has been reported to be a robust prognostic factor in TNBC [2]. The causal mechanisms underlying this immune response are unclear. It has been proposed that DNA damage with resultant activation of stimulator of

Methods

Results

Conclusion