Head and neck squamous cell carcinoma (HNSCC) affects more than 50,000 people annually. The five-year survival rate has not improved significantly in the last decades. In addition, many treatment modalities are associated with significant morbidity that negatively impacts survivors’ quality of life. Mutations in the HRAS oncogene are presented in 5-10% cases of HNSCC. Our group has established its critical importance for the growth and survival of HNSCC. HRAS protein undergoes crucial post-translational modifications prompted by the obligate addition of a farnesyl isoprenoid group, which is required for proper localization and insertion into the cell membrane, where it can engage effector molecules. FTIs block farnesylation and thus block HRAS activity. The FTI tipifarnib is under clinical evaluation for the treatment of HRAS mutant HNSCC, and preliminary findings showed some efficacy in this patient population. We sought strategies to enhance the efficacy of tipifarnib for the treatment of HRAS mutant HNSCC. We applied a novel CRISPR/Cas9 genetic screen to identify druggable targets that could be inhibited in combination with FTIs to improve treatment outcomes. We identified genes involved in regulating the ERK-MAPK and PI3K-AKT effector signaling pathways, autophagy regulation, chemokine signaling, and chromatin structure, that could potentially be targeted to increase tumor sensitivity to tipifarnib. Consistent with our genetic screening result of enhanced vulnerability to autophagy inhibition in tipifarnib-treated cells, we observed an increase in autophagic flux upon short-term treatment with tipifarnib alone, suggesting an attempt to compensate for nutrient stress. To overcome this effect, we tested the consequences of inhibiting autophagy pharmacologically in combination with tipifarnib. A panel of HRAS mutant HNSCC cell lines showed a synergistic increase in sensitivity to tipifarnib in combination with SBI-0206965 and MRT68921, two distinct preclinical inhibitors of the autophagy-promoting kinase ULK1. Clinical candidate ULK inhibitors are on the horizon. We suggest that the combination of tipifarnib with ULK inhibitors could be useful to sensitize HRAS mutant HNSCC to tipifarnib. Additional validation and mechanistic experiments are ongoing.
Citation Format: Sehrish-Javaid, Craig M. Goodwin, Kirsten L. Bryant, Samuel D. George, Victoria V. Nguyen, Kathryn N. Lambert, Andrew M. Waters, Channing J. Der, Adrienne D. Cox. CRISPR/Cas9 genetic screen identifies novel therapeutic strategies for treating HRAS mutant HNSCC with farnesyltransferase inhibitors (FTIs) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B15.