ATRX loss predicts poor outcomes and sensitizes to TEAD inhibition in soft tissue sarcomas

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Abstract

ATRX is one of the most frequently altered genes in sarcoma and encodes an ATP-dependent chromatin remodeler implicated in maintaining heterochromatin. However, ATRX alterations have not been leveraged for sarcoma treatment. We observed loss of ATRX protein in 14% of soft tissue leiomyosarcoma (STLMS, n =127), 53% of uterine leiomyosarcoma (ULMS, n = 95), 37% of undifferentiated pleomorphic sarcoma (UPS, n = 82), and 8% of dedifferentiated liposarcoma (DDLPS, n = 84). ATRX loss was associated with significantly worse outcomes in ULMS, UPS, and DDLPS. ATRX knockout in sarcoma cells increased proliferation in cooperation with TP53 deletion, chromatin remodeling, and enrichment of PRDM4 and NFIX transcription factor motifs. PRDM4 and NFIX knockdown in ATRX-mutant sarcoma lines resulted in reduced proliferation and invasion, suggesting an epistatic relationship. Consistent with the known and re-demonstrated functional relationship between PRMD4 and YAP1, ATRX loss activated YAP1-TEAD signaling, and ATRX-deficient cells and sarcoma xenografts were more sensitive to the TEAD inhibitors VT103 and IAG933. Overall, our results identify ATRX loss as a prognostic factor of worse outcomes, implicate the ATRX-PRDM4-YAP1-TEAD axis as an underlying mechanism, and suggest use of TEAD inhibition as a potential therapeutic strategy for ATRX-deficient sarcomas.

Authors

Ryan A. Denu, Anand K. Singh, Yingda Jiang, Zhao Zheng, Davis R. Ingram, Khalida M. Wani, Rossana Lazcano, Madison P. Ginn, Kumaren Anand, Bishal K. Singh, Jackson C. Ballard, Veena Kochat, Biji Chatterjee, William Padron, Sharon M. Landers, Angela D. Bhalla, Asha S. Multani, Sharvari Dharmaiah, Prit Benny Malgulwar, Yiming Cai, Jun Yao, Heather Lin, Jason T. Huse, Haoqiang Ying, Emily Z. Keung, Wei-Lien Wang, Anthony P. Conley, Shreyaskumar Patel, Neeta Somaiah, Ahsan S. Farooqi, Alexander J. Lazar, Elise F. Nassif Haddad, Keila E. Torres, Kunal Rai