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Figure S1 from Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

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posted on 2023-09-01, 08:40 authored by Alyssa C. Flint, Dana K. Mitchell, Steven P. Angus, Abbi E. Smith, Waylan Bessler, Li Jiang, Henry Mang, Xiaohong Li, Qingbo Lu, Brooke Rodriguez, George E. Sandusky, Andi R. Masters, Chi Zhang, Pengtao Dang, Jenna Koenig, Gary L. Johnson, Weihua Shen, Jiangang Liu, Amit Aggarwal, Gregory P. Donoho, Melinda D. Willard, Shripad V. Bhagwat, D. Wade Clapp, Steven D. Rhodes

Hallmark KRAS Pathway Heatmap and Top DEGs

Funding

Neurofibromatosis Therapeutic Acceleration Program (NTAP)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

United States Department of Health and Human Services

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National Institute of Neurological Disorders and Stroke (NINDS)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.

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