PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening
Jangsoon Lee,
Huey Liu,
Troy Pearson,
Toshiaki Iwase,
Jon Fuson,
Alshad S. Lalani,
Lisa D. Eli,
Irmina Diala,
Debu Tripathy,
Bora Lim,
Naoto T. Ueno
Affiliations
Jangsoon Lee
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Huey Liu
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Troy Pearson
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Toshiaki Iwase
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jon Fuson
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Alshad S. Lalani
Puma Biotechnology, Inc., Los Angeles, CA 90024, USA
Lisa D. Eli
Puma Biotechnology, Inc., Los Angeles, CA 90024, USA
Irmina Diala
Puma Biotechnology, Inc., Los Angeles, CA 90024, USA
Debu Tripathy
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Bora Lim
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Naoto T. Ueno
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions (p p p < 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC.
