RT Journal Article
SR Electronic
T1 Untangling the gene-epigenome networks: Timing of epigenetic regulation of gene expression in acquired cetuximab resistance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 136564
DO 10.1101/136564
A1 Genevieve Stein-O’Brien
A1 Luciane T Kagohara
A1 Sijia Li
A1 Manjusha Thakar
A1 Ruchira Ranaweera
A1 Hiroyuki Ozawa
A1 Haixia Cheng
A1 Michael Considine
A1 Alexander V Favorov
A1 Ludmila V Danilova
A1 Joseph A Califano
A1 Evgeny Izumchenko
A1 Daria A Gaykalova
A1 Christine H Chung
A1 Elana J Fertig
YR 2017
UL http://biorxiv.org/content/early/2017/05/10/136564.abstract
AB Widespread characterization of the genomic landscape of tumors has enabled precision treatment strategies. Despite significant advances in development of targeted therapies, patients with tumors sensitive to inhibitors often acquire resistance and succumb to their tumors. The timing and function of gene regulation responsible for resistance remain unknown. Clinical gains from the use of the anti-EGFR antibody, cetuximab, in head and neck squamous cell carcinoma (HNSCC) lead to FDA approval. However, cetuximab is not curative for HNSCC patients and a significant proportion acquire resistance to the treatment. A comprehensive characterization of the mechanisms resulting in acquired cetuximab resistance is critical to delineate new strategies to overcome resistance. To this end, we developed a novel time course analysis to study the in vitro progression of the molecular mechanisms resulting in acquired cetuximab resistance in HNSCC. Specifically, we collected multiple experimentally equivalent cultures over several generations in order to measure changes in gene expression, DNA methylation, and proliferation as resistance developed. This new long-term treatment protocol models the progression of acquired therapeutic resistance, including controls for clonal selection unrelated to treatment. The epigenetic regulation of FGFR1 expression emerged as the dominant mechanism of acquired therapeutic resistance in this system and was confirmed in primary tumors from The Cancer Genome Atlas (TCGA). The association of FGFR1 overexpression with cetuximab resistance is consistent with previous studies. Even in a subset of cetuximab stable resistant clones presenting substantial epigenetic heterogeneity, FGFR1 up-regulation in response to loss of promoter methylation emerged as a key regulator of resistance corroborating our pooled time course epigenetics data. Therefore, we hypothesize that alternative molecular mechanisms giving rise to EGFR inhibitor resistance could be overcome with the introduction of combined FGFR1 inhibition. Taken together, our time course profiling of DNA methylation and gene expression data provide a significant contribution to the characterization of mechanisms involved in acquired cetuximab resistance in HNSCC and provides new insights to alternative options for targeted therapy in this tumor type.