Abstract 4389: TSC1/2 mutations define a molecular subset of HCC with aggressive behavior and treatment implication

Abstract

We investigated the mutational landscape of mTOR signaling cascade in hepatocellular carcinomas (HCCs) with chronic hepatitis B (HBV) background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyper-activation in hepatocarcinogenesis. We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of TSC1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony formation assay in HCC cell lines and the treatment was further tested using our patient derived tumor xenograft (PDTX) models. Results: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n = 18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leading to more aggressive tumor behavior. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony forming ability upon Rapamycin treatment. With the use of the biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hyper-sensitivity towards Rapamycin treatment. Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyper-activation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signaling, with potential significance of effective specific drug therapy. Citation Format: Daniel Wai Ho, Lo Kong Chan, Yung Tuen Chiu, Iris Ming Xu, Ronnie Poon, Tan To Cheung, Chung Ngai Tang, Victor Tang, Irene Lo, Polly Lam, Derek Yau, Miao Xin Li, Chun Ming Wong, Irene O. L. Ng. TSC1/2 mutations define a molecular subset of HCC with aggressive behavior and treatment implication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4389. doi:10.1158/1538-7445.AM2017-4389

MicroRNA‐141‐3p regulates cellular proliferation, migration, and invasion in esophageal cancer by targeting tuberous sclerosis complex 1

“…Loss of TSC1 thereby promotes mTOR signaling which is involved in numerous processes important in oncogenesis such as enhanced cell growth and proliferation, angiogenesis, migration, and resistance to autophagy 13 . Although no role for TSC1 in the development or progression of esophageal cancer has yet been elucidated, loss or aberrant function of TSC1 has been demonstrated in several malignancies including, gastric cancer, prostate cancer, hepatocellular carcinoma, pancreatic neuroendocrine tumors, and melanoma 14–18 …”

“…13 Although no role for TSC1 in the development or progression of esophageal cancer has yet been elucidated, loss or aberrant function of TSC1 has been demonstrated in several malignancies including, gastric cancer, prostate cancer, hepatocellular carcinoma, pancreatic neuroendocrine tumors, and melanoma. [14][15][16][17][18] The goal of this study is to determine the expression levels of miR-141-3p and TSC1 in a panel of esophageal cancer cell lines and human esophageal cancer biopsy specimens. In addition, we will characterize the interaction between TSC1 mRNA and miR-141-3p in esophageal cancer cells using binding and functional assays.…”