Targeting eIF4A-dependent translation in genetically complex sarcoma
Young-Mi Kim, Prathibha Mohan, Urmila Sehrawat, Evan Seffar, Rafaela Muniz De Queiroz, Kalyani Chadalavada, Nikita Persaud, Tomoyo Okada, Anirudh Kulkarni, Jianan Lin, Nathalie Lailler, Shaleigh Smith, Bhumika Jadeja, Nicholas D. Socci, Zhengqing Ouyang, Hans-Guido Wendel, Samuel Singer
Young-Mi Kim, Prathibha Mohan, Urmila Sehrawat, Evan Seffar, Rafaela Muniz De Queiroz, Kalyani Chadalavada, Nikita Persaud, Tomoyo Okada, Anirudh Kulkarni, Jianan Lin, Nathalie Lailler, Shaleigh Smith, Bhumika Jadeja, Nicholas D. Socci, Zhengqing Ouyang, Hans-Guido Wendel, Samuel Singer
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Research Article Cell biology Oncology

Targeting eIF4A-dependent translation in genetically complex sarcoma

Abstract

Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient–derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.

Authors

Young-Mi Kim, Prathibha Mohan, Urmila Sehrawat, Evan Seffar, Rafaela Muniz De Queiroz, Kalyani Chadalavada, Nikita Persaud, Tomoyo Okada, Anirudh Kulkarni, Jianan Lin, Nathalie Lailler, Shaleigh Smith, Bhumika Jadeja, Nicholas D. Socci, Zhengqing Ouyang, Hans-Guido Wendel, Samuel Singer

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Figure 7

[-]CR-1-31B suppresses tumor growth of DDLS, MFS, and UPS xenografts.

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[-]CR-1-31B suppresses tumor growth of DDLS, MFS, and UPS xenografts. (A...
(A–C) Tumor growth DDLS8817 (A), MFS8000S (B), and UPS4746 (C) cell xenografts. Tumor cells were implanted s.c. into the flank of NSG mice and treated with either vehicle control or [-]CR-1-31B (0.5 mg/kg) after tumors reached ~100 mm3 in size. Dosing: for DDLS8817, i.v. twice a week for 4 weeks; for MFS8000S (n = 5 per group) and UPS4746 (n = 7 per group), i.p. 3 times a week for 4 weeks. Mean tumor volumes ± SD measured using calipers. (D) Weight of DDLS8817 xenograft-bearing mice treated with [-]CR-1-31B or vehicle. (E) Western blot for YAP, TAZ, and TEAD1 in DDLS8817 tumor lysates. Vinculin served as a loading control. (F) ImageJ quantification of YAP, TAZ, and TEAD1 protein levels normalized to vinculin (as in C). *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way repeated measures ANOVA in A–C and unpaired 2-tailed Student’s t test in F.