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USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma

ABSTRACT: Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoprotein c-MYC. Here, we show that genetic inactivation of USP28 induced regression of established murine LSCC lung tumors. We developed small molecule USP28 inhibitors that inhibit USP28 activity in the low nanomole range. While displaying considerable activity against the closest homologue USP25, these inhibitors showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-Myc proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

SUBMITTER: Adan Pinto-Fernandez

LAB HEAD: Benedikt Kessler

PROVIDER: PXD023339 | Pride | 2024-07-30

REPOSITORIES: Pride

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	FL1207_MSQ1831_20191007_APinto_APF10_1.raw	Raw
	FL1207_MSQ1831_20191007_APinto_APF10_2.raw	Raw
	FL1207_MSQ1831_20191007_APinto_APF10_3.raw	Raw
	FL1207_MSQ1831_20191007_APinto_APF1_1.raw	Raw
	FL1207_MSQ1831_20191007_APinto_APF1_2.raw	Raw

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