Abstract 5292: Glycogen synthase kinase-3 beta (GSK-3b) genomic alterations and increased programmed death-ligand 1 (PD-L1) expression in advanced malignancies
Authors: Borden Brittany A. , Xiu Joanne , Baca Yasmine , Ramos Pilar , Giles Francis J. , Mazar Andrew , Tavora Fabio , Safran Howard , El-Deiry Wafik S. , Carneiro Benedito A. 
Published: September 2020

Background: GSK-3β, a serine/threonine kinase, has been implicated in the pathogenesis of many cancers. Aberrant expression of GSK-3β promotes tumor growth and chemotherapy resistance. GSK-3β phosphorylates target pro-oncogenes (C-Jun and C-myc), as well as non-glycosylated forms of PD-L1 leading to its proteasome degradation (Li CW Nat Commun 2016). GSK-3β tumor genomic alterations have been described, yet are not well-characterized. Characterizing alterations and functional impact can guide patient selection for treatment with GSK-3β inhibitors and related combinations in clinical development, including 9-ING-41, a first-in-class, selective small molecule GSK-3β inhibitor currently in phase 1/2 clinical trial (NCT03678883).

Methods: Publicly-available tumor genomic data from cBioPortal was curated and analyzed. For each tumor with a GSK-3β alteration, histology and GSK-3β protein change/copy number variation (CNV) were obtained. A second cohort of tumors obtained from Caris Life Sciences (n=73,324) was interrogated for GSK-3β genomic alterations and PD-L1 expression (assessed via SP-142 antibody on tumor cells, cutoff used was 5%). Chi-square test was used to assess significance between PD-L1 expression of GSK3β-mutated tumors and that of GSK3β-wild type (wt) tumors.

Results: Of 46,237 cBioPortal tumors, 430 (1%) tumors had a GSK3β mutation or CNV. Similarly, of 73,324 samples from Caris, 819 (1%) tumors had GSK3β mutations. When combining the data from both cohorts, the histologies with most frequent GSK3β mutations were uterine endometrioid carcinoma (4%), non-melanoma skin cancer (3%), uterine neoplasms (3%), and melanoma (2%). Overall, top protein changes included R396Q (n=44), H310Q (n=40), R418C (n=16), and S215L (n=15). Of the top mutated loci, R96 (n=14) and R180 (n=12) are located in a key binding pocket for phosphoprotein GSK3β substrates.

The association between PD-L1 expression and GSK3β mutations was evaluated in 55,138 cases. The frequency of PD-L1 expression was significantly higher among GSK3β-mutated tumors compared to wt in colorectal cancer (8% vs. 4%, p=0.02), endometrial cancer (11% vs. 7%, p=0.05), melanoma (42% vs. 23%, p=0.01), ovarian surface epithelial carcinoma (20% vs. 7%, p=0.001), and uterine sarcoma (40% vs. 8%, p=0.005). Among these five histologies, 49 tumors had GSK3β mutations and were positive for PD-L1, and the top mutated residues were H310Q (n=5) and S215L (n=3).

Conclusions: In an assessment of over 100,000 tumor samples, GSK3β mutations were most frequently detected in uterine endometrioid carcinoma, non-melanoma skin cancer, uterine neoplasms, and melanoma. GSK3β mutations were associated with a higher frequency of PD-L1 expression in selected tumors. These results may have implications in the selection of patients for treatment with novel targeted therapies such as GSK3β inhibitors and PD-L1 inhibitors.

Citation Format: Brittany A. Borden, Joanne Xiu, Yasmine Baca, Pilar Ramos, Francis J. Giles, Andrew Mazar, Fabio Tavora, Howard Safran, Wafik S. El-Deiry, Benedito A. Carneiro. Glycogen synthase kinase-3 beta (GSK-3b) genomic alterations and increased programmed death-ligand 1 (PD-L1) expression in advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5292.