EGFR mediates activation of RET in lung adenocarcinoma with neuroendocrine differentiation characterized by ASCL1 expression

Kaustubh Bhinge, Lin Yang, Simone Terra, Aqsa Nasir, Prasuna Muppa, Marie Christine Aubry, Joanne Yi, Nafiseh Janaki, Irina V Kovtun, Stephen J. Murphy, Geoffrey Halling, Hamed Rahi, Aaron Mansfield, Mariza De Andrade, Ping Yang, George Vasmatzis, Tobias D Peikert, Farhad Kosari

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)27155-27165
Number of pages11
JournalOncotarget
Volume8
Issue number16
DOIs
StatePublished - 2017

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Epidermal Growth Factor Receptor
Adenocarcinoma
Epidermal Growth Factor
Protein Isoforms
Phosphorylation
Adenocarcinoma of lung
Survival
Receptor Protein-Tyrosine Kinases
Oncogenes
Immunoprecipitation
Small Interfering RNA
Transcription Factors
RNA
Messenger RNA
Mutation
Therapeutics

Keywords

  • ASCL1
  • EGFR
  • Lung cancer
  • Neuroendocrine
  • RET

ASJC Scopus subject areas

  • Oncology

Cite this

EGFR mediates activation of RET in lung adenocarcinoma with neuroendocrine differentiation characterized by ASCL1 expression. / Bhinge, Kaustubh; Yang, Lin; Terra, Simone; Nasir, Aqsa; Muppa, Prasuna; Aubry, Marie Christine; Yi, Joanne; Janaki, Nafiseh; Kovtun, Irina V; Murphy, Stephen J.; Halling, Geoffrey; Rahi, Hamed; Mansfield, Aaron; De Andrade, Mariza; Yang, Ping; Vasmatzis, George; Peikert, Tobias D; Kosari, Farhad.

In: Oncotarget, Vol. 8, No. 16, 2017, p. 27155-27165.

Research output: Contribution to journalArticle

Bhinge, Kaustubh ; Yang, Lin ; Terra, Simone ; Nasir, Aqsa ; Muppa, Prasuna ; Aubry, Marie Christine ; Yi, Joanne ; Janaki, Nafiseh ; Kovtun, Irina V ; Murphy, Stephen J. ; Halling, Geoffrey ; Rahi, Hamed ; Mansfield, Aaron ; De Andrade, Mariza ; Yang, Ping ; Vasmatzis, George ; Peikert, Tobias D ; Kosari, Farhad. / EGFR mediates activation of RET in lung adenocarcinoma with neuroendocrine differentiation characterized by ASCL1 expression. In: Oncotarget. 2017 ; Vol. 8, No. 16. pp. 27155-27165.
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abstract = "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.",
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T1 - EGFR mediates activation of RET in lung adenocarcinoma with neuroendocrine differentiation characterized by ASCL1 expression

AU - Bhinge, Kaustubh

AU - Yang, Lin

AU - Terra, Simone

AU - Nasir, Aqsa

AU - Muppa, Prasuna

AU - Aubry, Marie Christine

AU - Yi, Joanne

AU - Janaki, Nafiseh

AU - Kovtun, Irina V

AU - Murphy, Stephen J.

AU - Halling, Geoffrey

AU - Rahi, Hamed

AU - Mansfield, Aaron

AU - De Andrade, Mariza

AU - Yang, Ping

AU - Vasmatzis, George

AU - Peikert, Tobias D

AU - Kosari, Farhad

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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