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

Author:

Flint Alyssa C.1ORCID,Mitchell Dana K.1ORCID,Angus Steven P.123ORCID,Smith Abbi E.1ORCID,Bessler Waylan1ORCID,Jiang Li1ORCID,Mang Henry1ORCID,Li Xiaohong1ORCID,Lu Qingbo1ORCID,Rodriguez Brooke1ORCID,Sandusky George E.4ORCID,Masters Andi R.5ORCID,Zhang Chi6ORCID,Dang Pengtao6ORCID,Koenig Jenna7ORCID,Johnson Gary L.28ORCID,Shen Weihua9ORCID,Liu Jiangang9ORCID,Aggarwal Amit9ORCID,Donoho Gregory P.9ORCID,Willard Melinda D.9ORCID,Bhagwat Shripad V.9ORCID,Clapp D. Wade13ORCID,Rhodes Steven D.1310ORCID

Affiliation:

1. 1Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.

2. 2Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

3. 3Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana.

4. 4Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana.

5. 5Clinical Pharmacology Analytical Core, Indiana University School of Medicine, Indianapolis, Indiana.

6. 6Center for Computational Biology and Bioinformatics and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.

7. 7Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, Indiana.

8. 8UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

9. 9Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.

10. 10Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, Indiana.

Abstract

Abstract Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Funder

Neurofibromatosis Therapeutic Acceleration Program

National Cancer Institute

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of Neurological Disorders and Stroke

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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