Abstract 767
Background
HRAS is mutated or overexpressed in various cancers. Although numerous studies have demonstrated that HRAS mutations (HRASmut) promote chemoresistance in HNSCC, the effect of wild type HRAS overexpression (wtHRASov) on chemotherapy has not yet been studied. We sought: i. to investigate the repair capacity of wtHRASov tumors in cisplatin- induced damage and ii. to explore the cisplatin sensitizing effect of HRAS inhibitor tipifarnib.
Methods
Mutation/RNA and cisplatin IC50 data were retrieved from the Cancer Genome Atlas (TCGA) and COSMIC Cell Lines Project respectively. Modified Z-score was used to define HRAS overexpression. Patient derived xenografts (PDXs) were generated from treatment naïve HNSCC patients. Mutational and expression profile of tumor grafts was identified by whole exome sequencing, IHC, qRT-PCR and western blot analysis. Cisplatin or cisplatin combined with tipifarnib was used for PDX’s treatment. Therapy response was monitored by sequential tumor volume measurements over time.
Results
Our analysis of available RNA and cisplatin IC50 data from HNSCC cell lines demonstrated that wild type HRAS levels are positively correlated with cisplatin resistance. To identify resistance signatures in wtHRASov tumors, we compared the TCGA HNSCC transcriptomes of HRAS-altered (HRASmut or wtHRASov) and HRAS- unaltered tumors. Approximately 6% of HNSCCs were overexpressing HRAS, and there was only partial overlap with the 6% of HRASmut tumors. Moreover, ERCC1 was found highly upregulated in HRAS altered group and especially among wtHRASov subcluster. To further study the resistance of wtHRASov tumors, we generated a cohort of HNSCC PDXs and acquired their mutational, expression and chemosensitivity profile. PDX tumors harboring a profile similar to wtHRASov TCGA cluster exhibited a strong chemoresistant squamous phenotype associated with high ERCC1 levels. Interestingly, these tumors were resensitized to cisplatin when subjected to cisplatin/tipifarnib combinatorial treatment.
Conclusions
ERCC1 expression is a well-established biomarker for cisplatin resistance. Our study demonstrates that wtHRASov tumours represent a distinctive entity that strongly express ERCC1 and can be resensitized to cisplatin by tipifarnib.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Kura Oncology.
Disclosure
T. Rampias: Research grant / Funding (institution): Kura Oncology Company. All other authors have declared no conflicts of interest.
Resources from the same session
4692 - Immune cell biomarkers on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA NSCLC patients
Presenter: Raquel Laza-Briviesca
Session: Poster Display session 3
Resources:
Abstract
1707 - Clinical utility of precision immunoprofiling and monitoring of the tumor microenvironment using flow cytometry and CyTOF in patients with advanced NSCLC treated with atezolizumab: results from a phase II study for biomarker analysis (EPOC1702)
Presenter: Keisuke Kirita
Session: Poster Display session 3
Resources:
Abstract
3594 - Tumor mutation burden (TMB), PD-L1, IFN-γ signaling identify subgroups of patients (pts) who benefit from durvalumab (D, anti-PDL1) or D and tremelimumab (T, anti-CTLA4) treatment in urothelial bladder cancer (UC)
Presenter: Christophe Massard
Session: Poster Display session 3
Resources:
Abstract
744 - The decrease of TMB, TNB and HLA expression are the Mechanism of Drug Resistance of NSCLC to immunosuppressive PD-1/PD-l1.
Presenter: Sheng Yu
Session: Poster Display session 3
Resources:
Abstract
2350 - Eosinophilia during treatment of immune checkpoint inhibitors (ICIs) predicts succeeding onset of immune-related adverse events (irAEs)
Presenter: Rika Kizawa
Session: Poster Display session 3
Resources:
Abstract
5930 - A transcriptomic immunologic signature predicts favorable outcome in neoadjuvant chemotherapy treated triple negative breast tumors.
Presenter: Javier Pérez-peña
Session: Poster Display session 3
Resources:
Abstract
6127 - Alterations of TMB and TCR repertoires during Chemotherapy in East Asian lung cancer patients without TKI-related driver gene mutations
Presenter: Lele Song
Session: Poster Display session 3
Resources:
Abstract
1310 - Association of SCFA in gut microbiome and clinical response in solid cancer patients treated with andi-PD-1 antibody.
Presenter: Motoo Nomura
Session: Poster Display session 3
Resources:
Abstract
2286 - Extracellular matrix and tissue derived metabolites in a liquid biopsy identifies endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment
Presenter: Nicholas Willumsen
Session: Poster Display session 3
Resources:
Abstract
4107 - Pathologic scoring of pre-treatment H&E biopsies predicts overall survival in patients with metastatic clear cell renal cell carcinoma receiving nivolumab monotherapy
Presenter: Julie Stein
Session: Poster Display session 3
Resources:
Abstract