The PI3K inhibitor taselisib overcomes letrozole resistance in a breast cancer model expressing aromatase
Klaus P. Hoeflich1,*, Jane Guan1,*, Kyle A. Edgar1, Carol O’Brien2, Heidi Savage2, Timothy R. Wilson2, Richard M. Neve3, Lori S. Friedman1 and Jeffrey J. Wallin1
1 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA
2 Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
3 Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA
* These authors contributed equally to this manuscript
Correspondence:
Jeffrey Wallin, email:
Keywords: PI3K, Letrozole, Breast Cancer, GDC-0032, Akt
Received: February 29, 2016 Accepted: March 23, 2016 Published: March 25, 2016
Abstract
Letrozole is a commonly used treatment option for metastatic hormone receptor-positive (HR+) breast cancer, but many patients ultimately relapse. Due to the importance of phosphoinositide-3 kinase (PI3K) in breast cancer, PI3K inhibitors such as taselisib are attractive for combination with endocrine therapies such as letrozole. Taselisib was evaluated as a single agent and in combination with letrozole in a breast cancer cell line engineered to express aromatase. The combination of taselisib and letrozole decreased cellular viability and increased apoptosis relative to either single agent. Signaling cross-talk between the PI3K and ER pathways was associated with efficacy for the combination. In a secreted factor screen, multiple soluble factors, including members of the epidermal and fibroblast growth factor families, rendered breast cancer cells non-responsive to letrozole. It was discovered that many of these factors signal through the PI3K pathway and cells remained sensitive to taselisib in the presence of the soluble factors. We also found that letrozole resistant lines have elevated PI3K pathway signaling due to an increased level of p110α, but are still sensitive to taselisib. These data provide rationale for clinical evaluation of PI3K inhibitors to overcome resistance to endocrine therapies in ER+ breast cancer.
