In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 6056-6056
Abstract:
6056 Background: The DepMap genome-wide loss of function CRISPR screens offer new insight into gene dependencies in HPV(-) head and neck squamous cell carcinoma (HNSCC) cell lines. We aimed to leverage this data to guide preclinical studies by cataloging targetable dependencies and identifying ones predicted to offer a therapeutic window. We also aimed to identify targets representing potential synthetic lethalities by testing for associations between genetic alterations and dependency profile. Methods: DepMap was queried for gene probability and effect scores in cell lines from 77 tumors, including 62 HPV(-) HNSCCs plus 15 ESCCs, which have comparable etiology, genetic features, and tissue of origin. A probability score of ≥ 0.5 was used as the threshold for essentiality. Essential genes were selected for analysis by 3 criteria: (1) presence in ≥10% cell lines, (2) lack of dependency in CRISPR screens of normal human cell lineages, and (3) designation as druggable by the Drug-Gene Interaction Database. Gene set enrichment analysis was performed using the Hallmark Gene Sets. DepMap gene effect scores were used to prioritize targets likely to have a useful therapeutic window based on median scores greater than for EGFR (0.676), a target with established albeit modest utility for HNSCC. The Open Targets platform was used to identify targets with inhibitors used in trials for other cancers and/or nonmalignant diseases. Associations between dependencies and genetic alterations were defined using two-sample t-tests, with filter conditions of p 〈 0.05 and effect size ≥1. Results: The 231 genes meeting selection criteria had a median gene effect score of 0.56. The criteria captured targets of standard therapeutic agents including TYMS (5-FU), tubulin genes (paclitaxel), EGFR (cetuximab), plus known oncogenes like PIK3CA. GSEA showed enrichment of known oncogenic signaling pathways including PI3K/AKT and JAK/STAT, as well as hallmark cancer processes like DNA repair and apoptosis. 90% were not known oncogenes cataloged in the OncoKB Database. 45 genes had a median gene effect score between that of EGFR and the median for common essential genes, including 7 without known cancer-promoting roles: OTOP1, DHRSX, UTP11, MBTPS1, SLC25A3, PPIAL4G, and RBM10. 17% had inhibitors that reached a non-HNSCC phase II trial, including 10 targets not previously tested in cancer. Novel associations between dependencies and genetic alterations included DDX3X with NOTCH1mut, ITGB1 with CDKN2Amut, and ATP1A1 with HRASmut. Conclusions: We catalog targetable dependencies in cell line models of HNSCC. While well-studied targets were captured, many genes lacked known roles in malignancy. Targets of inhibitors tested in other diseases provide new tools to guide preclinical studies. Association of some dependencies with known molecular subgroups in HNSCC may enhance use of cell line models to personalize therapy.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2022.40.16_suppl.6056
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2022
detail.hit.zdb_id:
2005181-5
