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J Med Oncl Ther 2017 | Volume 2 Issue 4
Oncology and Biomarkers Summit
November 27-28, 2017 | Atlanta, USA
Annual Congress on
RET oncogene activation in lung adenocarcinoma with neuroendocrine differentiation is mediated
through EGFR
Farhad Kosari
Mayo Clinic, USA
Lung adenocarcinoma (AD) accounts for 40% of all
non-small cell lung cancers. Achaete-scute homolog 1
(ASCL1) is a neuroendocrine transcription factor specifically
expressed in 10-20% of lung AD with neuroendocrine (NE)
differentiation (NED). Our recent data demonstrated that
ASCL1 was 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 and lapatinib, 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. 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.
Speaker Biography
Farhad Kosari is an Assistant Professor in the Department of Molecular Medicine at
Mayo Clinic. His interests are in the discovery and development of clinically relevant
biomarkers for prostate and lung cancers. His domains of expertise are Bioinformatics
and Molecular Biology, particularly as related to the development of biomarker
based assays. His most recent project focus has been in lung adenocarcinomas with
neuroendocrine (NE) differentiation (ND-AD). Characterized by the expression of
ASCL1, these ND-ADs are a sizable subset of lung tumors that are largely understudied
and underappreciated. His group has recently discovered the main drivers in these
tumors and is currently investigating therapeutic options for patients with ND-AD.
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