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 journalArticlepeer-review

19 Citations (Scopus)


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
Issue number10
Publication statusPublished - 2018

Bibliographical note

Funding Information:
This work was supported by a Career Development Award from the University of Colorado Lung Cancer SPORE (funded by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) grant P50CA058187), a research grant from Pfizer, and funds from the Boettcher Foundation’s Webb-Waring Biomedical Research Program to RCD.

Publisher Copyright:
© Pilling et al.


  • ALK
  • MYC
  • ROS1
  • Synthetic lethality

ASJC Scopus subject areas

  • Oncology


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