Abstract 1089: Anti-tumor activity of selinexor is enhanced by palbociclib in preclinical models of HER2+ breast cancer

Abstract

Abstract Introduction: XPO1 (exportin-1/ CRM1) inhibitor selinexor (KPT-330) is the first-in-class, orally bioavailable, clinical stage SINE (Selective Inhibitor of Nuclear Export) compound with marked anti-tumor activity towards solid and hematological malignancies. This activity can be further enhanced by other therapeutic agents. We have previously shown strong synergistic preclinical activity of selinexor plus trastuzumab against HER2+ breast cancer. In cancer models of acquired resistance to HER2-targeted therapies, G1/S phase cell cycle regulators Cyclin D1 and CDK4/6 are inappropriately activated. We therefore investigated the combinatorial effect of selinexor plus palbociclib, a CDK4/6 inhibitor, in HER2+ breast cancer models as a treatment option for recurrent and relapsed HER2+ breast cancers. Methods: The effects of selinexor or palbociclib single agents or in combination were tested in vitro with BT474 HER2+ breast cancer cell line. Total RNA and protein was extracted from cell lysates and analyzed by qPCR and immunoblots. In vivo, a subcutaneous BT474 xenograft mouse model was treated with selinexor (5 mg/kg or 15 mg/kg; qodx3) or palbociclib (50 mg/kg or 150 mg/kg; qd) single agents or in combination. Tumor growth and body weights were monitored for 60 days. Tumors were harvested and analyzed by immunohistochemistry (IHC). Results: Selinexor plus palbociclib was highly effective in vitro and in vivo in BT474 breast cancer cells. In in vitro assays, selinexor or palbociclib single agents demonstrated inhibitory effects on cell proliferation and showed strong synergy when combined. In vivo, the combination resulted in significant survival benefit and enhanced tumor growth inhibition compared to vehicle or either single agent. IHC analysis of xenograft tumors showed synergistic inhibition of cell proliferation by selinexor plus palbociclib. The Ki67 proliferation index determined by IHC was 25% for vehicle control, 20% for selinexor, 7% for palbociclib and 2% for the combination. Based on IHC analysis, the synergistic anti-tumor activity of selinexor plus palbociclib was achieved at multiple levels of the CDK4/6 pathway. Selinexor treatment increased p21, p27 and Rb nuclear staining. Both p21 and p27 are inhibitors of CDK4/6 while Rb is a negative regulator of cell cycle progression. CDK4/6 phosphorylates and inactivates Rb, which allows cell cycle progression. In selinexor as well as palbociclib treated samples, phosphorylated Rb in the nucleus decreased, indicating a down-regulation of the CDK4/6 pathway. Conclusion: Selinexor plus palbociclib shows synergistic inhibition of cell proliferation in vivo and in vitro in HER2+ breast cancer cell line BT474 by down-regulation of CDK4/6 pathway. This combination therapy warrants further investigation as an effective treatment option for recurrent and relapsed HER2+ breast cancer. Citation Format: Hua Chang, Sharon Friedlander, Trinayan Kashyap, Boris Klebanov, Christian Argueta, Oscar A. Gonzalez, Erkan Baloglu, Yosef Landesman, Sharon Shacham, Margaret Lee, William Senapedis. Anti-tumor activity of selinexor is enhanced by palbociclib in preclinical models of HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1089. doi:10.1158/1538-7445.AM2017-1089