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Combination therapies for MPNSTs targeting RABL6A-RB1 signaling.

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.

SUBMITTER: Kohlmeyer JL

PROVIDER: S-EPMC7800773 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Combination therapies for MPNSTs targeting RABL6A-RB1 signaling.

Kohlmeyer Jordan L JL Gordon David J DJ Tanas Munir R MR Dodd Rebecca D RD Monga Varun V Darbro Benjamin W BW Quelle Dawn E DE

Oncotarget 20210105 1

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 retinobla ...[more]

PMID: 33456709

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