ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer

Amanda B. Pilling, Jihye Kim, Adriana Estrada-Bernal, Qiong Zhou, Anh T. Le, Katherine R. Singleton, Lynn E. Heasley, Aik-Choon Tan, James DeGregori, Robert C. Doebele

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

A subset of lung cancers is dependent on the anaplastic lymphoma kinase (ALK) oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated ALK+ NSCLC. Further analysis reveals that ALK regulates transcriptional expression of MYC and activates c-MYC transactivation of c-MYC target genes. Inhibition of MYC by RNAi or small molecules sensitizes ALK+ cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance.

Original languageEnglish
Pages (from-to)8823-8835
Number of pages13
JournalOncotarget
Volume9
Issue number10
DOIs
Publication statusPublished - 2018 Jan 1
Externally publishedYes

Fingerprint

Lung Neoplasms
Oncogenes
Survival
anaplastic lymphoma kinase
RNA Interference
Drug Resistance
Small Interfering RNA
Transcriptional Activation
Neoplasms
crizotinib
Genome
Genes

Keywords

  • ALK
  • MYC
  • NSCLC
  • ROS1
  • Synthetic lethality

ASJC Scopus subject areas

  • Oncology

Cite this

Pilling, A. B., Kim, J., Estrada-Bernal, A., Zhou, Q., Le, A. T., Singleton, K. R., ... Doebele, R. C. (2018). ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. Oncotarget, 9(10), 8823-8835. https://doi.org/10.18632/oncotarget.24260

ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. / Pilling, Amanda B.; Kim, Jihye; Estrada-Bernal, Adriana; Zhou, Qiong; Le, Anh T.; Singleton, Katherine R.; Heasley, Lynn E.; Tan, Aik-Choon; DeGregori, James; Doebele, Robert C.

In: Oncotarget, Vol. 9, No. 10, 01.01.2018, p. 8823-8835.

Research output: Contribution to journalArticle

Pilling, AB, Kim, J, Estrada-Bernal, A, Zhou, Q, Le, AT, Singleton, KR, Heasley, LE, Tan, A-C, DeGregori, J & Doebele, RC 2018, 'ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer', Oncotarget, vol. 9, no. 10, pp. 8823-8835. https://doi.org/10.18632/oncotarget.24260
Pilling AB, Kim J, Estrada-Bernal A, Zhou Q, Le AT, Singleton KR et al. ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. Oncotarget. 2018 Jan 1;9(10):8823-8835. https://doi.org/10.18632/oncotarget.24260
Pilling, Amanda B. ; Kim, Jihye ; Estrada-Bernal, Adriana ; Zhou, Qiong ; Le, Anh T. ; Singleton, Katherine R. ; Heasley, Lynn E. ; Tan, Aik-Choon ; DeGregori, James ; Doebele, Robert C. / ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. In: Oncotarget. 2018 ; Vol. 9, No. 10. pp. 8823-8835.
@article{8e42e7c64ebc48d993df04e058740243,
title = "ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer",
abstract = "A subset of lung cancers is dependent on the anaplastic lymphoma kinase (ALK) oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated ALK+ NSCLC. Further analysis reveals that ALK regulates transcriptional expression of MYC and activates c-MYC transactivation of c-MYC target genes. Inhibition of MYC by RNAi or small molecules sensitizes ALK+ cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance.",
keywords = "ALK, MYC, NSCLC, ROS1, Synthetic lethality",
author = "Pilling, {Amanda B.} and Jihye Kim and Adriana Estrada-Bernal and Qiong Zhou and Le, {Anh T.} and Singleton, {Katherine R.} and Heasley, {Lynn E.} and Aik-Choon Tan and James DeGregori and Doebele, {Robert C.}",
year = "2018",
month = "1",
day = "1",
doi = "10.18632/oncotarget.24260",
language = "English",
volume = "9",
pages = "8823--8835",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "10",

}

TY - JOUR

T1 - ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer

AU - Pilling, Amanda B.

AU - Kim, Jihye

AU - Estrada-Bernal, Adriana

AU - Zhou, Qiong

AU - Le, Anh T.

AU - Singleton, Katherine R.

AU - Heasley, Lynn E.

AU - Tan, Aik-Choon

AU - DeGregori, James

AU - Doebele, Robert C.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - A subset of lung cancers is dependent on the anaplastic lymphoma kinase (ALK) oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated ALK+ NSCLC. Further analysis reveals that ALK regulates transcriptional expression of MYC and activates c-MYC transactivation of c-MYC target genes. Inhibition of MYC by RNAi or small molecules sensitizes ALK+ cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance.

AB - A subset of lung cancers is dependent on the anaplastic lymphoma kinase (ALK) oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated ALK+ NSCLC. Further analysis reveals that ALK regulates transcriptional expression of MYC and activates c-MYC transactivation of c-MYC target genes. Inhibition of MYC by RNAi or small molecules sensitizes ALK+ cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance.

KW - ALK

KW - MYC

KW - NSCLC

KW - ROS1

KW - Synthetic lethality

UR - http://www.scopus.com/inward/record.url?scp=85041399074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041399074&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.24260

DO - 10.18632/oncotarget.24260

M3 - Article

AN - SCOPUS:85041399074

VL - 9

SP - 8823

EP - 8835

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 10

ER -