Abstract
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.
Highlights
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, deadly soft tissue sarcomas that lack effective therapies [1,2,3]
Recent observations demonstrate an essential role for an oncogenic GTPase, RABL6A, in promoting malignant peripheral nerve sheath tumors (MPNSTs) progression through hyperactivation of cyclin-dependent kinases (CDKs) and inactivation of the retinoblastoma (RB1) tumor suppressor
Because p27 protein loss is a frequent event associated with worse MPNST patient survival [13], we explored RABL6A expression and function in those tumors
Summary
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, deadly soft tissue sarcomas that lack effective therapies [1,2,3]. 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. We discuss the rationale and clinical benefits of inhibiting multiple RABL6A effectors, CDK4/6 and MEK kinases, in targeted combination therapies suitable for MPNSTs and other Rasdriven malignancies.
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