EGFR mediates activation of RET in lung adenocarcinoma with neuroendocrine differentiation characterized by ASCL1 expression
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Kaustubh Bhinge1, Lin Yang2, Simone Terra6, Aqsa Nasir2, Prasuna Muppa6, Marie Christine Aubry6, Joanne Yi6, Nafiseh Janaki2, Irina V. Kovtun3, Stephen J. Murphy1, Geoffrey Halling1, Hamed Rahi1, Aaron Mansfield5, Mariza de Andrade4, Ping Yang4, George Vasmatzis1, Tobias Peikert7, Farhad Kosari1
1Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
4Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
5Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
6Department of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
7Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
Farhad Kosari, email: firstname.lastname@example.org
Keywords: ASCL1, RET, EGFR, lung cancer, neuroendocrine
Received: April 10, 2016 Accepted: February 06, 2017 Published: February 24, 2017
Achaete-scute homolog 1 (ASCL1) is a neuroendocrine transcription factor specifically expressed in 10-20% of lung adenocarcinomas (AD) with neuroendocrine (NE) differentiation (NED). ASCL1 functions as an upstream regulator of the RET oncogene in AD with high ASCL1 expression (A+AD). RET is a receptor tyrosine kinase with two main human isoforms; RET9 (short) and RET51 (long). We found that elevated expression of RET51 associated mRNA was highly predictive of poor survival in stage-1 A+AD (p=0.0057). Functional studies highlighted the role of RET in promoting invasive properties of A+AD cells. Further, A+AD cells demonstrated close to 10 fold more sensitivity to epidermal growth factor receptor (EGFR) inhibitors, including gefitinib, than AD cells with low ASCL1 expression. Treatment with EGF robustly induced phosphorylation of RET at Tyr-905 in A+AD cells with wild type EGFR. This phosphorylation was blocked by gefitinib and by siRNA-EGFR. Immunoprecipitation experiments found EGFR in a complex with RET in the presence of EGF and suggested that RET51 was the predominant RET isoform in the complex. In the microarray datasets of stage-1 and all stages of A+AD, high levels of EGFR and RET RNA were significantly associated with poor overall survival (p < 0.01 in both analyses). These results implicate EGFR as a key regulator of RET activation in A+AD and suggest that EGFR inhibitors may be therapeutic in patients with A+AD tumors even in the absence of an EGFR or RET mutation.
Marie Christine Aubry
Irina V. Kovtun
Stephen J. Murphy
Mariza de Andrade
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