Modulation of mTOR and epigenetic pathways as therapeutics in gallbladder cancer

Abstract

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract, with extremely dismal prognosis. Limited therapeutic options are available for GBC patients. We used whole-exome sequencing of human GBC to identify the ErbB and epigenetic pathways as two vulnerabilities in GBC. We screened two focused small-molecule libraries that target these two pathways using GBC cell lines and identified the mTOR inhibitor INK-128 and the histone deacetylase (HDAC) inhibitor JNJ-26481585 as compounds that inhibited proliferation at low concentrations. Both significantly suppressed tumor growth and metastases in mouse models. Both synergized with the standard of care chemotherapeutic agent gemcitabine in cell lines and in mouse models. Furthermore, the activation of the mTOR pathway, measured by immunostaining for phosphorylated mTOR and downstream effector S6K1, is correlated with poor prognosis in GBC. Phosphorylated mTOR or p-S6K1 in clinical samples is an independent indicator for overall survival in GBC patients. Taken together, our findings suggest that mTOR inhibitors and HDAC inhibitors can serve as potential therapeutics for GBC, and the phosphorylation of mTOR and S6K1 may serve as biomarkers for GBC.

Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

“…Out of 92 articles, 30 were excluded due to: no data for adenocarcinoma of the gallbladder available (N = 12), overlapping cohorts (N = 8), the wrong type of article (N = 5), no genetic alteration frequency data available (N = 3), wrong study population (N = 1), and not written in English (N = 1). A total of 62 articles were included for final data extraction, describing a total of 3893 GBC samples from individual patients [ 18 , 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ,…”

“… ARID1A 14.3% 1/5 20% WES AC Japan Akita 2019 [ 48 ] 2/14 14% TS N.A. China Li 2017 [ 44 ] 2/47 4% WES AC China Yang 2021 [ 56 ] 2/25 8% targeted exome sequencing N.A. Korea Chae 2019 [ 79 ] 3/24 13% NGS N.A.…”

“… Japan Ebata 2021 [ 57 ] 19/144 13% WES AC India, Korea, Chile Pandey 2020 [ 46 ] 2/12 17% NGS N.A. China Li 2020 [ 47 ] 7/58 12% ultra-deep targeted NGS AC China Lin 2019 [ 70 ] 8/47 17% WES AC China Yang 2021 [ 56 ] 61/760 8% …”

“… America Okamura 2021 [ 27 ] 3/39 8% WES/WGS N.A. Japan Ebata 2021 [ 57 ] 4/47 9% WES AC China Yang 2021 [ 56 ] 22/144 15% WES AC India, Korea, Chile Pandey 2020 [ 46 ] 6/111 5% NGS N.A. America Mondaca 2019 [ 38 ] 5/12 42% …”

“… America Okamura 2021 [ 27 ] 0/32 0% targeted NGS AC Chile, Japan Narayan 2019 [ 73 ] 3/39 8% WES/WGS N.A. Japan Ebata 2021 [ 57 ] 4/47 9% WES AC China Yang 2021 [ 56 ] 3/50 6% NGS N.A. India Patel 2020 [ 39 ] 3/54 6% …”