Abstract 2840: CDK4/6 inhibitor PD-0332991 (palbociclib) promotes cell death and synergizes with CPT-11 in colorectal cancer under hypoxia in vitro

Abstract

Abstract We recently reported that a family of nucleoside analogues (sangivamycin-like molecules) can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK3-beta (Mayes et al., Cancer Research, 2011). We further reported that CDK inhibitors can destabilize HIF1-alpha regardless of VHL or p53 status or the presence of hypoxia (Warfel et al., Cell Cycle, 2013). In order to translate this knowledge into a cancer therapeutic strategy, we investigated the effects of CDK inhibition in colorectal cancer (CRC) cell lines with or without chemotherapy. PD-0332991 (Palbociclib) is a specific inhibitor of CDK4/6 that has been tested in numerous clinical trials for breast cancer, NSCLC, GBM, lymphoma, leukemia, in combination with 5-FU and oxaliplatin in solid malignancies (NCT01522989) or with cetuximab in head and neck cancer (NCT02101034). Palbociclib was approved by the FDA in 2015 in combination with letrozole as initial endocrine therapy for post-menopausal women with ER(+)/Her2(-) breast cancer. Little is known about the effects of CDK4/6 inhibition in CRC. We investigated the therapeutic effect and anti-proliferative mechanism of CDK4/6 inhibition in CRC. We used CellTiter-Glo assays to detect CRC cell viability and determined IC50 values (50% inhibitory concentration) of single drug through nonlinear regression analysis by GraphPad Prism software. The combination index (CI) of multiple drug combinations was identified with Compusyn analysis. We found that Palbociclib promotes cell death of CRC cells under hypoxia but not under normoxia where Palbociclib inhibited cell proliferation via the pRb pathway. These results suggest that the CDK4/6 inhibitor could regulate cell fate of CRC via different molecular mechanisms under hypoxia versus normoxia. We further found that Palbociclib can upregulate ERK/MAPK signaling under hypoxia, as compared with normoxia. The IC50 values of Palbociclib were generally higher under hypoxia (Mean ± SD: 10.54 ± 3.35 μM, N = 5) versus normoxia (Mean ± SD: 6.61 ± 0.85 μM, N = 5) in CRC cell lines. Thus, hypoxia promotes resistance of CRC cells toward the cytotoxic activity of the CDK4/6 inhibitor. We found that Palbociclib synergizes with CPT-11 much better than with either 5-FU or oxaliplatin against CRC cell lines with different molecular subtypes. Based on our findings that Palbociclib can promote cell death of CRC cells under hypoxia and synergizes with CPT11, further investigation is needed to assess the novel combination therapy against CRC. Citation Format: Jun Zhang, Lanlan Zhou, Shuai Zhao, David Dicker, Wafik S. El-Deiry. CDK4/6 inhibitor PD-0332991 (palbociclib) promotes cell death and synergizes with CPT-11 in colorectal cancer under hypoxia in vitro. [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 2840.