Abstract
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.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are a collection of diseases, diagnosed in ~59,000 people per year, and responsible for ~12,000 deaths in the U.S annually
Cetuximab has activity (Fig. 1b) in cisplatin-resistant patients[38], and we considered that cisplatin exposure may be altering the efficacy of palbociclib
human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) are a subset of tumors resulting from tobaccorelated exposure or viral infection
Summary
Head and neck squamous cell carcinomas (HNSCC) are a collection of diseases, diagnosed in ~59,000 people per year, and responsible for ~12,000 deaths in the U.S annually. The majority of HNSCC incidence (~40,000 cases) is attributed to tobacco exposure and smoking[1]. The molecular epidemiology of HNSCC is strongly determined by geographic location and anatomic subsite that dictates the genetics of these tumors. Oropharynx cancers are increasingly caused by human papillomavirus (HPV)[2,3]. HPVassociated tumors usually lack mutations or deletions in cell cycle inhibitory proteins because the cell cycle. HNSCC suggest that CDK4/6 has promise as a therapeutic target in HNSCC. Official journal of the Cell Death Differentiation Association
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