Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models.

Autor:	Daggubati V; Department of Radiation Oncology.; Department of Neurological Surgery.; Biomedical Sciences Graduate Program, and.; Medical Scientist Training Program, UCSF, San Francisco, California, USA., Hochstelter J; Department of Radiation Oncology.; Department of Neurological Surgery., Bommireddy A; Department of Radiation Oncology.; Department of Neurological Surgery., Choudhury A; Department of Radiation Oncology.; Department of Neurological Surgery.; Biomedical Sciences Graduate Program, and.; Medical Scientist Training Program, UCSF, San Francisco, California, USA., Krup AL; Department of Radiation Oncology., Kaur P; Department of Radiation Oncology., Tong P; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA., Li A; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA., Xu L; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA., Reiter JF; Department of Biochemistry and Biophysics, Cardiovascular Research Institute, Chan Zuckerberg Biohub, UCSF, San Francisco, California, USA., Raleigh DR; Department of Radiation Oncology.; Department of Neurological Surgery.; Biomedical Sciences Graduate Program, and.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2021 Mar 15; Vol. 131 (6).
DOI:	10.1172/JCI141171
Abstrakt:	Medulloblastoma is an aggressive pediatric brain tumor that can be driven by misactivation of the Hedgehog (HH) pathway. CDK6 is a critical effector of oncogenic HH signaling, but attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to single-agent molecular therapy. We identified mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma by performing orthogonal CRISPR and CRISPR interference screens in medulloblastoma cells treated with a CDK4/6 inhibitor and RNA-Seq of a mouse model of HH-associated medulloblastoma with genetic deletion of Cdk6. Our concordant in vitro and in vivo data revealed that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to ER stress and activation of the unfolded protein response (UPR). These pathways increased the activity of enzymes producing Smoothened-activating (SMO-activating) sterol lipids that sustained oncogenic HH signaling in medulloblastoma despite cell-cycle attenuation. We consistently demonstrated that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2, an enzyme producing SMO-activating lipids, additively blocked cancer growth in multiple mouse genetic models of HH-associated medulloblastoma. Our data reveal what we believe to be a novel pathway of resistance to CDK4/6 inhibition as well as a novel combination therapy to treat the most common malignant brain tumor in children.
Databáze:	MEDLINE
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