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

7 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

Keywords

  • ALK
  • MYC
  • NSCLC
  • ROS1
  • Synthetic lethality

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer'. Together they form a unique fingerprint.

  • Cite this

    Pilling, A. B., Kim, J., Estrada-Bernal, A., Zhou, Q., Le, A. T., Singleton, K. R., Heasley, L. E., Tan, A-C., DeGregori, J., & 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