Abstract 1864: In vivo efficacy of the PAK4 allosteric modulator KPT-9274 against a triple-negative breast cancer model

Abstract

Abstract The p21-activated kinases (PAK) belong to a family of serine threonine kinases that promote cell survival and play an important role in cell proliferation, cell cycle regulation and cell shape determination. There are six mammalian PAK proteins which can be subdivided into two groups by sequence homology and mode of activation- Group A PAKs consisting of PAK 1, 2 and 3 and Group B PAKs consisting of PAK 4, 5 and 6. We have found that PAK4 protein levels are elevated in breast cancer, including Her2 positive and triple negative breast cancers, while it is expressed at low levels in normal mammary tissue, making it an attractive drug target. PAK inhibitors are being tested for effectiveness against solid tumors, but generation of highly specific PAK4 inhibitors has been a challenge. Furthermore, PAK4 has been reported to have kinase-independent functions. Therefore inhibiting its kinase activity alone might not be sufficient in blocking its tumorigenic potential. Our lab has previously reported the effectiveness of PAK4 allosteric modulators (PAM; KPT-8752 and KPT-9274) against multiple breast cancer cell lines. These novel PAK4 inhibitors reduce steady state protein levels and were able to block cell growth, cell migration and induce apoptosis in breast cancer cell lines, without affecting the control cells. Here, we tested the efficacy of the orally bioavailable PAM, KPT-9274 against tumors formed by the triple negative breast cancer cell line, MDA-MB-231. Following six weeks of treatment with orally administered KPT-9274 (150mg/kg bidx4), there was almost a five-fold reduction in tumor volume and tumor weight in the treatment group as compared to the control group. The treatment did not significantly affect mice body weight. After six weeks of treatment, the tumors were excised and analyzed for PAK4 levels. We observed a significant decrease in PAK4 levels in excised tumors from the treatment group as compared to those from the control group. PAK1 levels were monitored to see any off-target effects, but their levels were unchanged. Our results indicate that PAK4 plays a key functional role in triple negative breast cancer and treatment with an orally administered KPT-9274 was capable of specifically binding and inhibiting PAK4, and consequently reducing tumor growth. Future studies analyzing the effects of KPT-9274 in blocking PAK4 mediated functions that promote tumorigenesis are ongoing. Additional studies of the effectiveness of KPT-9274 on mammary fat pad tumors formed by MDA-MB-231 and the ER positive cell line, MCF7 are under investigation. Citation Format: Chetan Rane, William Senapedis, Erkan Baloglu, Sharon Shacham, Audrey G. Minden. In vivo efficacy of the PAK4 allosteric modulator KPT-9274 against a triple-negative breast cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1864.