RABL6A is an essential driver of mpnsts that negatively regulates the rb1 pathway and sensitizes tumor cells to CDK4/6 inhibitors

Jordan L. Kohlmeyer, Courtney A. Kaemmer, Casey Pulliam, Chandra K. Maharjan, Allison Moreno Samayoa, Heather J. Major, Kendall E. Cornick, Vickie Knepper-Adrian, Rajesh Khanna, Jessica C. Sieren, Mariah R. Leidinger, David K. Meyerholz, K. D. Zamba, Jill M. Weimer, Rebecca D. Dodd, Benjamin W. Darbro, Munir R. Tanas, Dawn E. Quelle

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs. Experimental Design: We examined patient-matched MPNSTs and precursor lesions by RNA sequencing (RNA-Seq) and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor-suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors. Results: RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation, and RB1 activation. The growth-suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in an RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced antitumorigenic activity associated with potential MPNST cell redifferentiation. Conclusions: RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs.

Original languageEnglish (US)
Pages (from-to)2997-3011
Number of pages15
JournalClinical Cancer Research
Volume26
Issue number12
DOIs
StatePublished - Jun 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'RABL6A is an essential driver of mpnsts that negatively regulates the rb1 pathway and sensitizes tumor cells to CDK4/6 inhibitors'. Together they form a unique fingerprint.

Cite this