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Poster Display session 3

767 - Sensitizing HRAS overexpressing head and neck squamous cell carcinoma (HNSCC) to chemotherapy

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Tumour Site

Head and Neck Cancers

Presenters

Theodoros Rampias

Citation

Annals of Oncology (2019) 30 (suppl_5): v449-v474. 10.1093/annonc/mdz252

Authors

T. Rampias1, L. Hoxhallari2, M. Avgeris3, Z. Kanaki2, D. Telios4, E. Giotakis5, I. Giotakis4, A. Scorilas3, A. Psyrri6, A. Klinakis2

Author affiliations

  • 1 Biology, Biomedical research Foundation of the Academy of Athens (BRFAA), 11527 - Athens/GR
  • 2 Biology, Biomedical research Foundation of the Academy of Athens (BRFAA), 11527 - papagou, athens/GR
  • 3 Biology, National and Kapodistrian university of Athens, 15701 - Ilisia, Athens/GR
  • 4 2nd Department Of Otolaryngology, National and Kapodistrian University of Athens, General Hospital “Attikon”, 12462 - Chaidari/GR
  • 5 1st Department Of Otolaryngology, National and Kapodistrian University of Athens, University General Hospital “Hippocration”, 11527 - Athens/GR
  • 6 Internal Medicine/medical Oncology, Attikon University Hospital, 12462 - Athens/GR

Resources

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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.

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