Abstract B092: Assessment of glycogen synthase kinase-3 beta (GSK3β) genomic landscape to inform use of cancer therapeutics

Abstract

Abstract Background: GSK3β, a serine/threonine kinase, has been implicated in the pathogenesis of many cancers. It can act both as a tumor suppressor and a proto-oncogene. Overexpression of GSK3β promotes tumor growth and chemotherapy resistance. Genomic alterations in GSK3β have been identified in many cancer types but no comprehensive analysis is available. Characterization of both the landscape and functional implications of GSK3β alterations will be critical to guide patient selection for treatment with GSK3β inhibitors and related combinations in clinical development, including 9-ING-41, a first-in-class, small molecule potent selective GSK3β inhibitor currently in phase 1/2 clinical trial (NCT03678883). Methods: Publicly-available tumor genomic data was accessed from cBioPortal. Data from 159 studies, curated to exclude duplicate tumor samples, was analyzed. Tumor samples with a GSK3β genomic alteration, including mutations or copy number variations (CNV), were included for analysis. For each tumor, histology, GSK3β protein change or type of CNV, and predicted functional impact of mutation were obtained. Results: 42,199 tumor samples were assessed for GSK3β genomic alterations that were identified in approximately 1% of the specimens (n=414). GSK3β mutations, fusions, frameshift insertions/deletions, and splice site mutations, were present in 211 (0.5%) tumors. Missense mutations were most prevalent (67%). Of 117 unique missense mutations, 68% were predicted to be deleterious by SIFT criteria, while 66% were predicted to be at least possibly damaging by Polyphen-2. Of all mutations, 58% were found in the GSK3β kinase domain. Of all 211 tumors, 10 (5%) had mutations in one of three key GSK3β residues that form a binding pocket for the phosphate group of a primed substrate (R96, R180, and K205). R96 and R180 were found to be of the most commonly mutated residues in this dataset. Cancers most frequently containing a GSK3β mutation were uterine endometrioid carcinoma (n=30, 5% of all cBioPortal uterine endometrioid carcinoma samples included in 42,199 analyzed tumors), melanoma (n=24, 2%) colorectal adenocarcinoma (n=30, 1%), and lung adenocarcinoma (n=19, 1%). GSK3β gene fusions were identified in 17 cases with prostate cancer being the most frequent cancer type (53%). GSK3β CNV, including amplification and homozygous deletion, were found in 217 (0.5%) tumors. Cancers most frequently containing GSK3β CNV were cervical squamous cell carcinoma (n=15, 6%), lung squamous cell carcinoma (n=36, 5%), head and neck squamous cell carcinoma (n=15, 3%), serous ovarian cancer (n=15, 3%), prostate adenocarcinoma (n=40, 2%), and breast invasive ductal carcinoma (n=18, 1%). Conclusions: GSK3β genomic alterations are present in a subset of several malignancies (1-6%). Commonly mutated residues include those that form the binding pocket for the phosphate group of a primed GSK3β substrate, and the majority of GSK3β mutations occur in the kinase domain. The most commonly mutated histologies are distinct from those with GSK3β CNV. Ongoing additional analyses include assessment of the GSK3β genomic landscape in an expanded cohort and functional and pathway analyses to investigate potential biomarkers for treatment response or resistance to selective GSK3β inhibitor 9-ING-41. Citation Format: Brittany A. Borden, Lorin Crawford, Howard P. Safran, Francis J. Giles, Wafik S. El-Deiry, Benedito A. Carneiro. Assessment of glycogen synthase kinase-3 beta (GSK3β) genomic landscape to inform use of cancer therapeutics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B092. doi:10.1158/1535-7163.TARG-19-B092