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CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition
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Priya K. Gopalan1, Andres Gordillo Villegas1,5, Chunxia Cao1, Mary Pinder-Schenck2,6, Alberto Chiappori2, Wei Hou3,7, Maria Zajac-Kaye4, Alison M. Ivey1 and Frederic J. Kaye1
1 Department of Medicine, University of Florida, Gainesville, FL, USA
2 Moffitt Cancer Center, Tampa, FL, USA
3 Department of Biostatistics, University of Florida, Gainesville, FL, USA
4 Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, USA
5 Current address: Sangamo Therapeutics, Richmond, CA, USA
6 Current address: Merck, Philadelphia, PA, USA
7 Current address: Division of Epidemiology and Biostatistics, Stony Brook University, Stony Brook, NY, USA
Frederic J. Kaye, email: [email protected]
Keywords: non-small cell lung cancer; CDK 4/6; palbociclib; mTOR; clinical trial
Received: September 29, 2018 Accepted: November 16, 2018 Published: December 21, 2018
Aberrant activation of CDK4/6 kinase is the most common somatic event in non-small cell lung cancer (NSCLC). Palbociclib is a highly specific CDK4/6 inhibitor shown to inhibit cell cycle progression and promote cellular senescence. We conducted a phase 2 clinical trial of palbociclib in 19 previously-treated patients with advanced NSCLC. Only patients with p16-null staining by immunohistochemistry and documented tumor progression were eligible. The primary endpoint was tumor response rate. Palbociclib therapy alone was well-tolerated. Of 16 evaluable patients who received > 1 month of therapy, there were no objective responses. However, 8 patients (50%) with previously progressive NSCLC had stable disease (SD) lasting a range of 4-10.5 months. Median overall survival (OS) for all cases was 5.1 months, and median overall survival for the subset of patients with SD was 16.6 months. We also performed preclinical testing of palbociclib in combination with 13 different targeted or cytotoxic chemotherapeutic agents using a cell viability assay. Only the combination of palbociclib and mTOR inhibitors resulted in synergistic growth inhibition, particularly in tumors carrying RAS mutations. Our findings warrant further clinical investigation of the combination of palbociclib and mTOR inhibitors, especially in patients carrying activated RAS mutations.
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