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

doi:10.1158/1078-0432.CCR-19-2706

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RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors

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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, …

Clinical cancer research, Vol.26(12), pp.2997-3011

06/15/2020

DOI: 10.1158/1078-0432.CCR-19-2706

PMCID: PMC7299809

PMID: 32086342

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Abstract

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. 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. RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G 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 an RABL6A-dependent manner and suppressed MPNST growth . Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced antitumorigenic activity associated with potential MPNST cell redifferentiation. 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.

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Title: Subtitle: RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors
Creators: Jordan L Kohlmeyer - University of Iowa
Courtney A Kaemmer - University of Iowa
Casey Pulliam - University of Iowa
Chandra K Maharjan - University of Iowa
Allison Moreno Samayoa - University of Iowa
Heather J Major - University of Iowa
Kendall E Cornick - University of Iowa
Vickie Knepper-Adrian - University of Iowa
Rajesh Khanna - University of Arizona
Jessica C Sieren - University of Iowa
Mariah R Leidinger - University of Iowa
David K Meyerholz - University of Iowa
K D Zamba - University of Iowa
Jill M Weimer - Sanford Research
Rebecca D Dodd - University of Iowa
Benjamin W Darbro - University of Iowa
Munir R Tanas - University of Iowa
Dawn E Quelle - University of Iowa
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.26(12), pp.2997-3011
DOI: 10.1158/1078-0432.CCR-19-2706
PMID: 32086342
PMCID: PMC7299809
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Grant note: P30 ES005605 / NIEHS NIH HHS T32 GM067795 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS P50 CA174521 / NCI NIH HHS
Language: English
Date published: 06/15/2020
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Biostatistics; Medical Genetics and Genomics; Radiation Oncology; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984186559202771

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