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.
Subject(s)
Cisplatin/administration & dosage , Cyclin-Dependent Kinase 4/genetics , Proto-Oncogene Proteins c-myc/genetics , Squamous Cell Carcinoma of Head and Neck/drug therapy , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cetuximab/administration & dosage , Cisplatin/adverse effects , Drug Resistance, Neoplasm/drug effects , Female , Heterografts , Humans , Male , Mice , Papillomaviridae/genetics , Papillomaviridae/pathogenicity , Papillomavirus Infections/drug therapy , Papillomavirus Infections/genetics , Papillomavirus Infections/pathology , Protein Kinase Inhibitors/administration & dosage , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathologyABSTRACT
BACKGROUND: Recent orthopedic research has questioned the effect of opioid use on surgical outcomes. This study investigated this in the context of arthroscopic rotator cuff repair. We hypothesized that preoperative opioid use would be associated with inferior outcomes and greater postoperative opioid requirements. METHODS: A database query identified adult patients with full-thickness or partial-thickness supraspinatus tears surgically treated between 2011 and 2015. Preoperative and postoperative outcomes scores (active range of motion [AROM], American Shoulder and Elbow Surgeons [ASES], Constant scores, Simple Shoulder Test [SST], and visual analog scale [VAS] for pain) and postoperative opioid use were retrospectively recorded. Patients with less than 2 years of follow-up data at the time of the retrospective review were contacted for prospective ASES, SST, and VAS data collection. RESULTS: A total of 200 patients, 44 of whom received opioids preoperatively, were identified for inclusion. Patients prescribed preoperative opioids had consistently inferior preoperative and postoperative outcomes scores; however, the magnitudes of improvement were not significantly different between groups. Postoperatively, patients in the preoperative opioid group received 1.91 (95% confidence interval, 1.31-2.78) times more opioids over a postoperative course of treatment that was 2.73 (95% confidence interval, 1.62-4.59) times longer. In addition to having a greater proportion of women, this group also had significantly higher rates of certain comorbidities, including back pain, depression, degenerative joint disease, and chronic pain conditions. CONCLUSIONS: All patients demonstrated significant improvements in outcomes scores after surgical repair that were not significantly different between groups. However, patients taking opioids preoperatively did not ultimately reach the same level of functionality and had substantially greater opioid requirements postoperatively.
