PD 0332991, a selective cyclin D kinase 4/6 inhibitor, sensitizes lung cancer cells to treatment with epidermal growth factor receptor tyrosine kinase inhibitors

// Minghui Liu 1, * , Song Xu 1, 2, * , Yuli Wang 2, * , Ying Li 2 , Yongwen Li 2 , Hongbing Zhang 1 , Hongyu Liu 2 , Jun Chen 1, 2 1 Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, 300052, Tianjin, China 2 Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, 300052, Tianjin, China * These authors have contributed equally to this work Correspondence to: Jun Chen, email: huntercj2004@yahoo.com Hongyu Liu, email: liuhongyu123@hotmail.com Keywords: lung cancer, EGFR-TKIs, PD 0332991, gefitinib, drug resistance Received: April 05, 2016      Accepted: September 27, 2016      Published: November 04, 2016 ABSTRACT Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge to targeted therapy for non-small cell lung cancer (NSCLC). We investigated whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse EGFR-TKI resistance in human lung cancer cells and explored the underlying mechanisms. We found that PD 0332991 potentiated gefitinib-induced growth inhibition in both EGFR-TKI-sensitive (PC-9) and EGFR-TKI-resistant (PC-9/AB2) cells by down-regulating proliferation and inducing apoptosis and G0/G1 cell cycle arrest. Tumor xenografts were then used to verify the effects of PD 0332991 in vivo . Mice treated with a combination of PD 0332991 and gefitinib had the fastest tumor regression and delayed relapse. Tumors from mice receiving the combination treatment exhibited down-regulated proliferation, up-regulated apoptosis, and less angiogenesis. Finally, lung adenocarcinoma patients with acquired resistance to EGFR-TKIs were given an exploratory treatment of PD 0332991. One patient with gefitinib resistance exhibited clinical remission after treatment with PD 0332991. These findings suggest PD 0332991 reverses acquired EGFR-TKI-resistance in NSCLC cells, and may provide a novel treatment strategy for NSLSC patients with EGFR-TKI resistance.