Squamous cell carcinoma driven by human papillomavirus (HPV) is more sensitive to DNA-damaging therapies than its HPV-negative counterpart. Here, we show that p16, the clinically used surrogate for HPV positivity, renders cells more sensitive to radiotherapy via a ubiquitin-dependent signaling pathway, linking high levels of this protein to increased activity of the transcription factor SP1, increased HUWE1 transcription, and degradation of ubiquitin-specific protease 7 (USP7) and TRIP12. Activation of this pathway in HPV-positive disease led to decreased homologous recombination and improved response to radiotherapy, a phenomenon that can be recapitulated in HPV-negative disease using USP7 inhibitors in clinical development. This p16-driven axis induced sensitivity to PARP inhibition and potentially leads to “BRCAness” in head and neck squamous cell carcinoma (HNSCC) cells. Thus, these findings support a functional role for p16 in HPV-positive tumors in driving response to DNA damage, which can be exploited to improve outcomes in both patients with HPV-positive and HPV-negative HNSCC. Significance: In HPV-positive tumors, a previously undiscovered pathway directly links p16 to DNA damage repair and sensitivity to radiotherapy via a clinically relevant and pharmacologically targetable ubiquitin-mediated degradation pathway.

Doxorubicin, a widely used anthracycline antibiotic, has been a cornerstone in cancer chemotherapy since the 1960s. In addition to doxorubicin, anthracycline chemotherapy medications include daunorubicin, idarubicin, and epirubicin. For many years, doxorubicin has been the chemotherapy drug of choice for treating a broad variety of cancers. Despite its efficacy, doxorubicin therapy is hindered by serious side effects, primarily cardiotoxicity, and the challenges of drug resistance. Recent research has focused on optimizing doxorubicin’s therapeutic index by developing cardioprotective strategies, such as dexrazoxane, and utilizing non-invasive monitoring techniques to reduce cardiac risk. To counteract drug resistance, innovative formulations like nanoparticle-based delivery systems, enhance targeted drug delivery and overcome cellular resistance mechanisms. Furthermore, using combination approaches involving immunotherapy, photodynamic therapy, and genetic modulation, offer promising synergies to maximize tumor eradication. Personalized approaches, supported by pharmacogenomics and predictive biomarkers, are enhancing individualized treatment regimens, aiming to increase effectiveness and minimize toxicity. Future research on doxorubicin focuses on developing advanced drug delivery systems, such as nanoparticle and liposomal formulations, to enhance targeted delivery, minimize systemic toxicity, and improve therapeutic precision. Efforts are also underway to design combination therapies that integrate doxorubicin with immunotherapies, photodynamic approaches, and gene-based treatments, aiming to overcome resistance and increase tumor-specific effects. These advancements signify a transition toward more personalized and effective doxorubicin-based cancer therapies, prioritizing reduced side effects and improved patient outcomes. This article focusses on the ongoing innovations aimed at maximizing the therapeutic potential of doxorubicin while addressing its limitations.

Purpose: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear. Experimental Design: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy. Results: We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage, and repressed homologous recombination and nonhomologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. The mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared with wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized an HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors. Conclusions: FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.

Full Western Blot Images 1 from FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner