CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition
Musicant, A. M.; Parag-Sharma, K.; Gong, W.; Sengupta, M.; Chatterjee, A.; Henry, E. C.; Tsai, Y.-H.; Hayward, M.; Sheth, S.; Betancourt, R.; Hackman, T.; Padilla, R. J.; Parker, J. S.; Giudice, J.; Flaveny, C. A.; Hayes, D. N.; Amelio, A. L.
Show abstract
Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1 splice variant PGC-14, which regulates PPAR{gamma}-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPAR{gamma}inhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.
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