RABL6A discovered to regulate AKT-mTOR signaling pathway in patients with PNETs

Philadelphia, PA, October 20, 2017—Researchers have discovered that retinoblastoma-like protein 6 A (RABL6A) is an essential activator of protein kinase B (AKT)-mechanistic targets of rapamycin (mTOR) signaling in pancreatic neuroendocrine tumor (PNET) cells, and its expression may control the response to AKT inhibitor treatment, according to study results presented at the North American Endocrine Tumor (NANETS) 2017 Symposium, in Philadelphia, PA.  

“We’re studying different cancer pathways in neuroendocrine tumor cells, and we focused on the AKT-mTOR pathway because that is what is clinically treated in patients. They have drugs that inhibit AKT, but more commonly, drugs that inhibit mTOR, which is everolimus,” explained senior author Dawn Quelle, PhD, associate professor, Pharmacology, University of Iowa, Iowa City, IO.

“We wanted to connect our particular protein with that pathway because we had evidence that they were linked at the molecular level,” she added.

Dr. Quelle and colleagues sought to better understand the pathways vital to the pathogenesis of PNET to identify novel PNET biomarkers as well as drug targets and improve both diagnosis and treatment in these patients.

They discovered a new oncogenic thymidine phosphorylase (TPase), RABL61, and that it is amplified in PNETS. RABL6a is a protein necessary for PNET cell proliferation and survival via regulation of retinoblastoma (Rb1) activity, as well as other unknown cancer pathways.

In their study, they discovered that the depletion of RABL6A worked to significantly hinder AKT activation selectively via reduced S473 phosphorylation, as well as AKT signaling. In addition, they observed that mTORC2 complexes remain intact and active in RABL6A-depeleted PNET cells.  RABL6A was also found to regulate AKT-S473 phosphorylation via protein phosphatase PP2A. Finally, Dr. Quelle and colleagues observed that AKT activation rescued G1 phase arrest of the RABL6A-depleted PNET cells.

“If you need to use anti-cancer drugs, you have to find potentially new combinations that will kill the cells better and effectively. So that’s what we hope the identification of these new targets might lead into new combination therapies,” said Dr. Quelle.

“Both for clinicians and from my own perspective as a basic scientist, we need to speak with each other so that we learn from each other. I need to know what is currently in the clinic so that I can identify targets or new targets that are in relevant pathways. And they need to interact with basic science as well to understand what it is that we’re learning about these pathways, so that then they can use the most rational combination therapies for treating patients,” she noted.

In the future, Dr. Quelle and fellow researchers have several paths of research planned, including the testing of new combinations of PNET therapies that target AKT, mTOR, and CDKs to assess whether RABL6A affects responses to therapy, as well as determining whether RABL6A levels in patient NETs are correlated with AKT-mTOR status in tissue microarrays.