Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair-defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC. Significance: This study uses innovative machine learning-based approaches to derive models that predict the effect of DNA repair defects on treatment outcome in HNSCC.

Generating New FANCA-Deficient HNSCC Cell Lines by Genomic Editing Recapitulate the Cellular Phenotypes of Fanconi Anemia

“…5). This result is in line with reports indicating that HNSCC with DNA repair defects display features of invasive disease (Bakhoum et al, 2018, Bhide et al, 2016, Essers et al, 2019. More specifically, increased in vitro invasiveness of sporadic HNSCC cell lines where FA genes have been knocked-down with shRNA was also reported (Romick-Rosendale et al, 2016).…”

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

“…In addition, hypoxia has been also implicated in tumor cell invasiveness, facilitating dissemination, and has been therefore associated with metastasis formation, a role that is also evident from our DM analyses. Similarly, we have recently shown that HNSCC cell lines with DNA crosslink repair defects are more migratory and invasive (63), a feature that may explain the association with DM prognosis but could also result in a greater regional spread and failure of locoregional control.…”

“…Treatment could however alter prognosis in subsets of patients. For instance, patients with tumors with DNA crosslink repair defects benefit most from a high cumulative cisplatin dose (63). Similarly, possible immune cell infiltration links could depend on treatment.…”

“…Our own studies conducted in HPV-negative advanced HNSCC revealed an important role for EMT and DNA crosslink (CL) repair defects in treatment outcome and these prediction models for mesenchymal characteristics and tumor cell DNA crosslink repair defects (11). "HNSCC-EMT" and (12) "MMConly, " were therefore included in this analysis and are referred to as "EMT" and "DNA CL repair" in this manuscript (63,64). Most of these biological factors have been tested individually, predominantly in univariable analyses and in different settings in previous studies; however their mutual correlations and possible dependence between them are unknown.…”

“…Our previous studies emphasized the important role of functional and genetic DNA crosslink repair defects in HNSCC (61,62) and provided the basis for machine learning generated models that predicted such DNA repair defects in clinical samples (63). The expression based DNA repair defect prediction models revealed an association with metastasis in HNSCC and linked DNA repair defects to migratory and invasive behavior in HNSCC cell lines (63). Given the relevance of Epithelial to Mesenchymal Transition (EMT) in many cancer types, we also developed a HNSCC-specific EMT model that classifies HNSCC according to epithelial or mesenchymal characteristics (64).…”