Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models
Vikas Daggubati, … , Jeremy F. Reiter, David R. Raleigh
Vikas Daggubati, … , Jeremy F. Reiter, David R. Raleigh
Published January 21, 2021
Citation Information: J Clin Invest. 2021;131(6):e141171. https://doi.org/10.1172/JCI141171.
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Concise Communication Metabolism Oncology

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

Abstract

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.

Authors

Vikas Daggubati, Jordan Hochstelter, Anirudh Bommireddy, Abrar Choudhury, Alexis Leigh Krup, Pervinder Kaur, Pakteema Tong, Amy Li, Libin Xu, Jeremy F. Reiter, David R. Raleigh

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Figure 2

Combination molecular therapy blocking CDK4/6 and SMO-activating lipid synthesis attenuates the growth of HH-associated medulloblastomas.

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Combination molecular therapy blocking CDK4/6 and SMO-activating lipid s...
(A) H&E staining of sagittal mouse medulloblastoma sections after 14 days of treatment, from P21 to P35. Scale bar: 1 mm. (B) Quantification of P35 tumor to brain weight ratios for Math1-Cre SmoM2C mice. Data are shown as the mean ± SEM. #P = 0.02, §P = 0.0003, and *P < 0.0001. n = 59. (C) Quantification of P35 tumor to brain weight ratios for Math1-Cre Ptch1C/C mice. Data are shown as the mean ± SEM. †P = 0.01 and ††P = 0.0002. n = 32. (D) P35 mouse medulloblastoma brain micrographs. Dashed lines represent the vehicle control tumor area overlaid onto other treatment conditions. Scale bar: 5 mm. (E) Kaplan-Meier survival curves for mice with HH-associated medulloblastoma. Tukey’s multiple-comparison test (B and C) and a log-rank test (E) were used for statistical comparisons.