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
5678 - Nanomaterials Augmented LDI-TOF-MS for Hepatocellular Carcinoma Diagnosis and Classification
Presenter: Jian Zhou
Session: Poster Display session 3
Resources:
Abstract
2436 - Development and Validation of an RNA-Seq Assay for Gene Fusions Detection in Formalin-Fixed Paraffin-Embedded Samples
Presenter: Hua Dong
Session: Poster Display session 3
Resources:
Abstract
5271 - A Pilot Study to Implement an Artificial Intelligence (AI) System for Gastrointestinal Cancer Clinical Trial Matching
Presenter: Zhaohui Jin
Session: Poster Display session 3
Resources:
Abstract
4787 - A Blinded Comparison of Patient Treatments to Therapeutic Options Presented by an Artificial Intelligence-based Clinical Decision-support system
Presenter: Suthida Suwanvecho
Session: Poster Display session 3
Resources:
Abstract
5744 - OncOS: scalable and accurate next-generation sequencing analytics for precision oncology and personalized patient care
Presenter: Joe Thompson
Session: Poster Display session 3
Resources:
Abstract
3752 - The association between wearable device physical activity metrics and performance status in oncology: a systematic review
Presenter: Milan Kos
Session: Poster Display session 3
Resources:
Abstract
5820 - SomaticNET: neural network evaluation of somatic mutations in cancer
Presenter: Geoffroy Dubourg-Felonneau
Session: Poster Display session 3
Resources:
Abstract
4771 - Is there a role for Next-generation sequencing (NGS) profiling on metastatic non-colorectal gastrointestinal carcinomas (MNCGIC) in developing countries? A single center experience.
Presenter: Mauricio Ribeiro
Session: Poster Display session 3
Resources:
Abstract
1209 - Metastatic Cancer Whole-Exome Sequencing in daily practice
Presenter: Manon Réda
Session: Poster Display session 3
Resources:
Abstract
5702 - Genomic-Guided Individualized Precision Therapy in Refractory Metastatic Solid Tumor Patients with Extensively Poor Performance Status: A Chinese single institutional prospective observational real-world study
Presenter: Haitao Wang
Session: Poster Display session 3
Resources:
Abstract