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

Autor:	Pilling AB; University of Colorado Cancer Center, Aurora, CO, USA.; Henry Ford Cancer Institute, Detroit, MI, USA., Kim J; University of Colorado Cancer Center, Aurora, CO, USA., Estrada-Bernal A; University of Colorado Cancer Center, Aurora, CO, USA., Zhou Q; University of Colorado Cancer Center, Aurora, CO, USA., Le AT; University of Colorado Cancer Center, Aurora, CO, USA., Singleton KR; University of Colorado Cancer Center, Aurora, CO, USA., Heasley LE; University of Colorado Cancer Center, Aurora, CO, USA., Tan AC; University of Colorado Cancer Center, Aurora, CO, USA., DeGregori J; University of Colorado Cancer Center, Aurora, CO, USA., Doebele RC; University of Colorado Cancer Center, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Jan 16; Vol. 9 (10), pp. 8823-8835. Date of Electronic Publication: 2018 Jan 16 (Print Publication: 2018).
DOI:	10.18632/oncotarget.24260
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST RCD has received honorarium, consulting fees and a research grant from Pfizer and consulting fees from OxOnx.
Databáze:	MEDLINE
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