Correction: Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma
Year: 2024
Type: erratum
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.
Source: Clinical Cancer Research
Authors: 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
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Eli Lilly and Company, Johns Hopkins University, Riley Children's Foundation, National Institutes of Health, School of Medicine, Indiana University, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G4615147670, Predictive Modeling of the EGFR-MAPK pathway for Triple Negative Breast Cancer Patients, Illuminating Function of the Understudied Druggable Kinome, Developmental and Hyperactive Ras Tumor (DHART) SPORE, T cells in neurofibroma pathogenesis and malignanttransformation, Indiana University Melvin and Bren Simon Comprehensive Cancer Center Support Grant
OpenAlex ID: W4396556606