Combination therapies for MPNSTs targeting RABL6A-RB1 signaling
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Jordan L. Kohlmeyer1,2, David J. Gordon3,6, Munir R. Tanas1,4,6, Rebecca D. Dodd1,5,6, Varun Monga5,6, Benjamin W. Darbro3,6 and Dawn E. Quelle1,2,3,6
1 Molecular Medicine Graduate Program, University of Iowa, Iowa City, Iowa, USA
2 Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, Iowa, USA
3 Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
4 Department of Pathology, University of Iowa, Iowa City, Iowa, USA
5 Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
6 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
|Dawn E. Quelle,||email:||email@example.com|
Keywords: MPNST; RABL6A-RB1 signaling; CDK4/6 and MEK inhibitors; Ras; targeted cancer therapy
Received: December 15, 2020 Accepted: December 16, 2020 Published: January 05, 2021
Precision medicine relies on a detailed molecular understanding of disease pathogenesis. Here, we consider urgently needed therapeutic options for malignant peripheral nerve sheath tumors (MPNSTs) based on emerging insights into druggable pathway alterations found to drive this deadly cancer. Recent observations demonstrate an essential role for an oncogenic GTPase, RABL6A, in promoting MPNST progression through hyperactivation of cyclin-dependent kinases (CDKs) and inactivation of the retinoblastoma (RB1) tumor suppressor. Monotherapies with CDK4/6 inhibitors have shown limited efficacy and durability in pre-clinical studies of MPNSTs and in clinical studies of other tumors. Therefore, we discuss the rationale and clinical benefits of inhibiting multiple RABL6A effectors, particularly CDK4/6 and MEK kinases, in targeted combination therapies suitable for MPNSTs and other Ras-driven malignancies.
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