CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

SUMMARYMucoepidermoid 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-1α splice variant PGC-1α4, which regulates PPARγ-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 PPARγinhibition 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.