Priority Research Papers:

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 and Robert C. Doebele _

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Oncotarget. 2018; 9:8823-8835. https://doi.org/10.18632/oncotarget.24260

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Amanda B. Pilling1,2, Jihye Kim1, Adriana Estrada-Bernal1, Qiong Zhou1, Anh T. Le1, Katherine R. Singleton1, Lynn E. Heasley1, Aik Choon Tan1, James DeGregori1 and Robert C. Doebele1

1 University of Colorado Cancer Center, Aurora, CO, USA

2 Henry Ford Cancer Institute, Detroit, MI, USA

Correspondence to:

Robert C. Doebele, email:

Keywords: ALK; ROS1; NSCLC; MYC; synthetic lethality

Received: July 28, 2017 Accepted: January 09, 2018 Published: January 16, 2018


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.

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