Role Of Egfr-As1 Lncrna In Growth Factor Addiction And Treatment Response In Squamous Cell Cancers

Abstract Squamous-cell cancers (SCCs) represent one of the commonest lethal malignancy worldwide. Despite evidence demonstrating that majority are addicted to Epidermal Growth Factor Receptor (EGFR)-signaling, targeting with monoclonal antibodies or tyrosine-kinase inhibitors (TKIs) has been met with limited success. We recently demonstrated that TKI-sensitivity is modulated by a long non-coding RNA (lncRNA) situated in the antisense strand of EGFR (EGFR-AS1). ‘Synonymous' alterations in EGFR-AS1 affected TKI-response in patient-derived models, and could be used to predict response in a small patient cohort. The lncRNA likely functions in cis by altering EGFR splicing, favouring expression of a truncated EGFR isoform (isoform D), with previously unknown function. Importantly, mediation of this effect requires EGFR ligand derived from paracrine or autocrine sources. Remarkably, even modest EGFR-AS1 knockdown showed profound effects on TKI sensitivity and tumor growth in vivo; the latter suggesting lncRNA-addiction. TKI-resistance models were established from patient-derived lines, through serial passaging with sub-lethal drug doses. Detailed analyses of four of these models demonstrate alterations that affect each of the steps involved in this addiction pathway: ligand binding, EGFR-AS1 expression/amplification and isoform D expression. Based on our mechanistic insights, we propose that patient-response to EGFR inhibitors is contingent on establishing a comprehensive suite of inter-related biomarkers as delineated here. This data also supports a novel therapeutic approach that involves modulating a lncRNA and/or splice variants of a well-established oncogenic driver. Citation Format: Daniel SW Tan, Fui-Teen Chong, Hui-Sun Leong, Shen Yon Toh, Dawn P. Lau, Xue Lin Kwang, Xiaoqian Zhang, Gek San Tan, Anders J. Skanderup, Tony KH Lim, Ramanuj Dasgupta, N Gopalakrishna Iyer. Role of EGFR-AS1 lncRNA in growth factor addiction and treatment response in squamous cell cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2591.