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E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor

Oncogene volume 40, pages 6614–6626 (2021)Cite this article

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Abstract

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients’ samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)—the main effector of muscular atrophy in cachexia—resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.

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Fig. 1: RAS/MAPK and PI3K/mTOR pathways are critical effectors of the KIT oncogenic program for GIST cell survival and proliferation.
Fig. 2: Whole-transcriptome studies identify that FBXO32 is universally highly expressed in GIST in response to KIT or KIT-downstream RAS/MAPK and PI3K/mTOR pathways inhibition.
Fig. 3: Atrogin-1 expression is transcriptionally regulated by FOXO3a in GIST.
Fig. 4: Atrogin-1 promotes GIST cells survival in response to targeted KIT inhibition.
Fig. 5: Atrogin-1 overexpression is induced upon imatinib treatment in GIST patients.
Fig. 6: In vitro and in vivo preclinical evaluation of the combined inhibition of imatinib and TAK-243 in the imatinib-sensitive GIST-T1 and GIST882 cell models.
Fig. 7: Model of the role of Atrogin-1 in GIST. Left, under KIT constitutive activation, KIT-downstream pathways phosphorylate and retain FOXO3a in the cytoplasm.

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Acknowledgements

This project was funded by the 2014 SARC International Career Development Award (SARC Sarcoma Spore 1U54CA168512–01), Fundación Mari Paz Jiménez Casado, FERO Foundation, Spanish Society of Medical Oncology (SEOM), PERIS SLT006/17/221, ISCIII PI16/01371 and PI19/01271, all to C.S. ISCIII FI20/00275 (to DG-P), and a Ph.D. fellowship from the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT) (to DFP-J). AE-C is funded by ISCIII PT17/0009/0019 and co-funded by FEDER. We thank the Cellex Foundation for providing facilities and equipment.

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Author notes

  1. These authors contributed equally: Joaquín Arribas, César Serrano.

Authors and Affiliations

  1. Sarcoma Translational Research Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Alfonso García-Valverde, Jordi Rosell, David Gómez-Peregrina, Daniel F. Pilco-Janeta, Iván Olivares-Rivas & César Serrano

  2. Institute of Molecular Biology, Mainz, Germany

    Sergi Sayols

  3. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Daniel F. Pilco-Janeta & Jonathan A. Fletcher

  4. Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital /CSIC/University of Sevilla/CIBERONC, Sevilla, Spain

    Enrique de Álava

  5. Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Sevilla, Spain

    Enrique de Álava

  6. Medical Oncology Department, Hospital Clinic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Barcelona, Spain

    Joan Maurel

  7. Medical Oncology Service, Institut Català d’Oncologia, Girona, Spain

    Jordi Rubió-Casadevall

  8. CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    Anna Esteve & Marta Gut

  9. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Anna Esteve & Marta Gut

  10. Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    Claudia Valverde, Joan Carles & César Serrano

  11. Institut Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Institut Català d’Oncologia, Badalona, Spain

    Jordi Barretina

  12. Sarcoma and Bone Cancer Treatment Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    George D. Demetri

  13. Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA

    George D. Demetri

  14. Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain

    Joaquín Arribas

  15. Growth Factors Laboratory, Vall d’Hebron Institute of Oncology (VHIO) and CIBERONC, Barcelona, Spain

    Joaquín Arribas

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  1. Alfonso García-Valverde
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Contributions

All authors contributed to this study. Conception and design: AG-V, GDD, JAF, JA, and CS. Data acquisition: AG-V, JR, DFP-J, IO-R, EA, JM, JR-C, AE, MG, and CS. Data analysis: AG-V, JR, SS, DGP, EA, AE, MG, and CS. Data interpretation: AG-V, JR, SS, DGP, CV, JC, JAF, JA, and CSG. Writing: AG-V and CS. All authors revisited and approved the draft.

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Correspondence to César Serrano.

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Competing interests

SS has received consulting fees (advisory role) from Boehringer Ingelheim. DFP-J has received travel grants from Pfizer, Roemmers, and Roche. MG has received consulting fees from Roche and Illumina. CV has received consulting fees (advisory role) from Lilly, PharmaMar, Pfizer, Eisai, Bayer, Mundipharma, GlaxoSmithKline, and travel grants from PharmaMar, Lilly, Novartis, Bayer, and Pfizer. CS has received research funding (institution) from Karyopharm, Pfizer, Inc, Deciphera Pharmaceuticals, and Bayer AG; consulting fees (advisory role) from CogentBio, Immunicum AB, Deciphera Pharmaceuticals and Blueprint Medicines; payment for lectures from Bayer AG and Blueprint Medicines; and travel grants from PharmaMar, Pfizer, Bayer AG, Novartis, and Lilly. The remaining authors declare no competing interests.

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García-Valverde, A., Rosell, J., Sayols, S. et al. E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor. Oncogene 40, 6614–6626 (2021). https://doi.org/10.1038/s41388-021-02049-0

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