Abstract A43: RB pathway disruption by the CDK4/6 inhibitor palbociclib enhances responses to chemotherapy in squamous cell lung cancer

Lung cancer remains one of the leading causes of cancer-related mortality. Squamous cell lung cancer (SqCLC) is the second most common subtype of non-small cell lung cancer (NSCLC). Despite recent development of effective targeted therapeutic agents for lung adenocarcinoma, patients with SqCLC often receive conventional cytotoxic chemotherapy as this cancer subtype lacks genomic alterations that can be targeted by personalized medicine. Hence, novel approaches that enhance the efficacy of chemotherapy will benefit treatment outcomes in this patient population. CDK inhibitors comprise a class of drugs that targets the dysregulated cell cycle in malignant cells. Treatment of tumor cells with the CDK4/6 inhibitor palbociclib inhibits tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Based on promising clinical trial data, palbociclib in combination with letrozole was granted accelerated approval by the US FDA for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. In this preclinical study, we explored the effect of palbociclib on several chemotherapies (taxanes, platins, and antimetabolites) in preclinical models of SqCLC. Because the activity of chemotherapy generally requires cell cycle progression, careful combination/sequencing of this class of drugs with CDK inhibitors may be important to achieve synergy as well as avoid potential antagonism. To obtain optimal activity of palbociclib and chemotherapy combinations, we investigated several combination/sequencing regimens (concurrent, chemotherapy followed by palbociclib or the reverse sequence) in several SqCLC cell lines. We did not encounter antagonism of chemotherapy-mediated cytotoxicity by palbociclib in any of the tested regimens. Rather, we observed robust combinatorial anti-cancer cell activity in all settings. Combination of palbociclib with chemotherapy was associated with reduction of RB phosphorylation and FOXM1 protein levels, and the induction of p21. Our studies demonstrated that, while palbociclib partially antagonized chemotherapy-induced apoptosis, it significantly synergized with chemotherapy to induce cell cycle arrest as well as a senescence-like phenotype. Cells pretreated with palbociclib plus cisplatin or palbociclib plus docetaxel displayed less cell growth upon drug removal compared to those treated with monotherapies. Finally, palbociclib treatment that followed docetaxel, nab-paclitaxel or cisplatin treatment significantly enhanced the antitumor activity of the chemotherapies in several cell line-derived or patient-derived xenograft models. Our results suggest that treatment with optimal palbociclib and chemotherapy combination/sequencing could lead to better clinical outcomes for SqCLC patients. Citation Format: Ping Wei, Joan Cao, Goldie Lui, Hui Wang, Konstantinos Tsaparikos, David Shields, Kim Arndt, Paul Rejto, Todd VanArsdale, James Hardwick. RB pathway disruption by the CDK4/6 inhibitor palbociclib enhances responses to chemotherapy in squamous cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A43.