Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma

• Published in: Clinical cancer research 2023-09, Vol.29 (17), p.3438-3456
• Main Authors: Flint, Alyssa C., Mitchell, Dana K., Angus, Steven P., Smith, Abbi E., Bessler, Waylan, Jiang, Li, Mang, Henry, Li, Xiaohong, Lu, Qingbo, Rodriguez, Brooke, Sandusky, George E., Masters, Andi R., Zhang, Chi, Dang, Pengtao, Koenig, Jenna, Johnson, Gary L., Shen, Weihua, Liu, Jiangang, Aggarwal, Amit, Donoho, Gregory P., Willard, Melinda D., Bhagwat, Shripad V., Wade Clapp, D., Rhodes, Steven D.
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-22-2854

Plexiform neurofibromas (PNF) represent a major source of morbidity in persons with neurofibromatosis type 1 (NF1). There remains an unmet need to develop new and effective treatment strategies for PNF given that a significant proportion of patients do not exhibit durable responses to currently available therapies. Using an integrated multi-omic approach, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Concordantly, combined CDK4/6 and ERK1/2 inhibition demonstrated robust synergism and enhanced anti-tumor activity in a mouse model of NF1-associated PNF that has demonstrated high fidelity in forecasting therapeutic responses in clinical trials. Collectively, these results demonstrate the utility of systems biology coupled with preclinical modeling to rationally inform novel single agent and combination therapies in the treatment of rare diseases.