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Cell Death Dis. 2019 Nov 14;10(11):867. doi: 10.1038/s41419-019-2098-8.

Cisplatin exposure causes c-Myc-dependent resistance to CDK4/6 inhibition in HPV-negative head and neck squamous cell carcinoma.

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Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Medical College of Wisconsin, Milwaukee, WI, USA.
Pfizer Oncology Research Unit, La Jolla, CA, USA.
Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Memorial Sloan-Kettering Cancer Center, Monmouth, NJ, USA.


The loss of p16 is a signature event in Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) that leads to increased Cyclin Dependent Kinase 4/6 (CDK) signaling. Palbociclib, a CDK4/6 inhibitor, is active for the treatment of a subset of HNSCC. In this study, we analyzed patient response data from a phase I clinical trial of palbociclib in HNSCC and observed an association between prior cisplatin exposure and CDK inhibitor resistance. We studied the effects of palbociclib on cisplatin-sensitive and -resistant HNSCC cell lines. We found that while palbociclib is highly effective against chemo-naive HNSCC cell lines and tumor xenografts, prior cisplatin exposure induces intrinsic resistance to palbociclib in vivo, a relationship that was not observed in vitro. Mechanistically, in the course of provoking a DNA damage-resistance phenotype, cisplatin exposure upregulates both c-Myc and cyclin E, and combination treatment with palbociclib and the c-Myc bromodomain inhibitor JQ1 exerts a synergistic anti-growth effect in cisplatin-resistant cells. These data show the benefit of exploiting the inherent resistance mechanisms of HNSCC to overcome cisplatin- and palbociclib resistance through the use of c-Myc inhibition.

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