LZTR1Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL

Author:

Ko Aram1ORCID,Hasanain Mohammad1ORCID,Oh Young Taek1ORCID,D'Angelo Fulvio1ORCID,Sommer Danika1ORCID,Frangaj Brulinda1ORCID,Tran Suzanne2ORCID,Bielle Franck2ORCID,Pollo Bianca3ORCID,Paterra Rosina3ORCID,Mokhtari Karima4ORCID,Soni Rajesh Kumar5ORCID,Peyre Matthieu46ORCID,Eoli Marica3ORCID,Papi Laura7ORCID,Kalamarides Michel46ORCID,Sanson Marc68ORCID,Iavarone Antonio191011ORCID,Lasorella Anna191112ORCID

Affiliation:

1. 1Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.

2. 2Sorbonne Université, INSERM U1127, CNRS UMR 7225, Brain Institute, ICM, AP-HP, University Hospital La Pitié Salpêtrière-Charles Foix, Laboratory of Neuropathology, Paris, France.

3. 3Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

4. 4Sorbonne Université, INSERM U1127, CNRS UMR 7225, Brain Institute, ICM, AP-HP, University Hospital La Pitié Salpêtrière-Charles Foix, Neurosurgery Service, Paris, France.

5. 5Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

6. 6Sorbonne Université, INSERM U1127, CNRS UMR 7225, Brain Institute, ICM, AP-HP, University Hospital La Pitié Salpêtrière-Charles Foix, Service of Neurology 2-Mazarin, Equipe lLNCC, Paris, France.

7. 7The Department of Experimental and Clinical, Medical Genetics Unit, Biomedical Sciences “Mario Serio,” University of Florence, Florence, Italy.

8. 8Onconeurotek Tumor Bank, Brain and Spinal Cord Institute ICM, 75013 Paris, France.

9. 9Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.

10. 10Department of Neurology, Columbia University Medical Center, New York, New York.

11. 11Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

12. 12Department of Pediatrics, Columbia University Medical Center, New York, New York.

Abstract

AbstractLZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer.Significance:EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer.This article is highlighted in the In This Issue feature, p. 517

Funder

National Cancer Institute

Children's Tumor Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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