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Endometrial carcinoma is the most dominant gynecological tumor worldwide. Familial risk of endometrial cancer has been reported but little is known about the predisposition genes. Here we focused on a family with high incidence of cancer, aiming to identify potential markers with low allele frequency and high disease-causing probability. Whole-genome sequencing was performed with available DNA from 4 family members: one healthy control and 3 endometrial cancer patients. We analyzed the non-synonymous variations in the coding region expressed in 3 of the patients but not in the healthy control. The variations with high allele frequencies in Taiwanese population were excluded. Five potential candidates, KMT2D, PCDHA8, COG5, RAPGEF3 and PFDN1, were identified as heterozygous mutations predisposed to endometrial cancer. In addition, we demonstrated that PCDHA8 and COG5 genes play crucial roles in cell proliferation in endometrial cancer cells. Notably, KMT2D (lysine methyltransferase 2D) is highly mutated in the tumors of endometrial cancer. An interaction between mutated KMT2D and other candidate genes may explain the high risk of cancer formation in this family. These results validate the potential markers of endometrial cancer and create opportunities for therapeutic applications and personalized prevention. Citation Format: Yu-Cheh Chiang, Ting-Fang Lee, Yung-Feng Lin, Hui-Ying Weng, Shih-Feng Tsai, Cheng-Wen Wu. Identify the predisposition genes to endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4168.

PAK1 is an important oncogene involved in the progression of a variety of cancer types including lung cancer. Although PAK1 inhibition is shown to suppress tumor progression, specific PAK1 inhibitors are not available due to the complex structure and insufficient understanding of this protein. In an attempt to find TAZ (WW domain-containing transcription regulator 1) regulated tumor suppressor, a member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is observed to suppress PAK1 phosphorylation. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). Immunohistochemistry staining in lung cancer tissue revealed prolonged disease-free survival in high ANKRD52 expressing cases. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expressed ANKRD52 decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. Upregulated PAK1 phosphorylation was detected in the knockdowns of ANKRD52 or PP6. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interactions with PP6 and dephosphorylation of PAK1. Citation Format: Ting-Fang Lee, Yin-Pu Liu, Yen-Fan Lin, Chong-Fang Hsu, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis through dephosphorylation of PAK1 in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1782.

Cancer metastasis is an ultimate challenge in our effort to fight cancer as a life-threatening disease. A member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is studied here to be involved in the regulation of lung adenocarcinoma metastasis. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). Immunohistochemistry staining in lung adenocarcinomas tissues revealed low ANKRD52 expressing in stage-IV patients compared to those in stages I to III. Overexpressed ANKRD52 prevented lung cancer formation in the xenograft model. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expression decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. The regulation of PAK1 phosphorylation by the ANKRD52-PP6 complex is essential to cell mobility. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interacting with PP6 leading to PAK1 dephosphorylation. Citation Format: Ting-Fang Lee, Yen-Fan Lin, Ying-Pu Liu, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5508.

As a leading cause of cancer-related deaths, metastasis is the ultimate challenge in our effort to fight cancer as a life-threatening disease. A member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is studied here to be involved in the regulation of lung adenocarcinoma metastasis. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). This study aimed to investigate the anti-metastatic roles of ANKRD52 in lung adenocarcinoma. Immunohistochemistry staining in lung cancer tissue revealed prolonged disease-free survival in high ANKRD52 expressing cases. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expressed ANKRD52 decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. Upregulated PAK1 phosphorylation was detected in ANKRD52 or PP6 knockdowns. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interactions with PP6 and dephosphorylation of PAK1. Citation Format: Yen-Fan Lin, Ying-Pu Liu, Ting-Fang Lee, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis through dephosphorylation of PAK1 in lung adenocarcinoma [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 4843. doi:10.1158/1538-7445.AM2017-4843

Epidermal growth factor receptor (EGFR) mutation is prevalently expressed in lung adenocarcinoma cases and acts as one of the major driving oncogenes. EGFR tyrosine kinase inhibitors (TKIs) have been used in patients with EGFR-mutant as an effective targeted therapy in lung adenocarcinoma, but drug resistance and tumor recurrence inevitably occurs. Recently, Yes-associate protein (YAP) has been reported to promote multiple cancer cell properties, such as promoting cell proliferation, EMT and drug resistance. This study investigated the roles of YAP in TKI-resistant lung adenocarcinoma. In TKI-sensitive cells, enhanced YAP expression leads to TKI resistant. Also, upregulated YAP expression and activation were detected in long term TKI-induced resistant cells. With reduced YAP expression using shRNA or YAP inhibitors, TKI-resistant cells become TKI-sensitive. Moreover, combined EGFR TKI and an YAP inhibitor statin, prolonged survival among lung cancer patients analyzed by Taiwan National Health Insurance Research database. These observations revealed the importance of YAP in promoting TKI-resistance and combined YAP inhibition can be a potential therapy delaying the occurrence of TKI-resistance in lung adenocarcinoma. Citation Format: Ting-Fang Lee, Yu-Chi Tseng, Cheng-Wen Wu. Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas [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 1189. doi:10.1158/1538-7445.AM2017-1189

Epidermal growth factor receptor (EGFR) mutations are found in lung adenocarcinomas leading to tumor cells proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) that block EGFR activity are effective therapeutics for EGFR-mutant lung adenocarcinoma patients, but TKI-resistance inevitably occurs. The YES-associated protein (YAP) transcription coactivator has been implicated as an oncogene and is amplified in human cancers and provides tumor cells strong proliferation and survival cues. This study investigated the roles of YAP in lung adenocarcinoma by exploring its regulation and functions mediated by EGFR signaling. Using lung adenocarcinoma cell lines, we detected enhanced YAP expression and activity mediated by EGFR signaling due to enhanced protein stability. The Src family protein YES was involved in EGFR-regulated YAP expression. The YAP/YES pathway was crucial for proliferation in EGFR-dependent cells. Small molecules that reduced YAP levels by mechanisms bypassing EGFR were effective in killing EGFR-dependent cells including EGFR T790M, the major cause of TKI-resistance. These observations unveiled the significance of YAP in EGFR mutant lung adenocarcinomas and identified YAP as an promising therapeutic target for EGFR-dependent lung adenocarcinoma patients, including those with EGFR T790M-caused TKI resistance. Citation Format: Ting-Fang Lee, Yu-Chi Tseng, Ying-Pu Liu, Yu-Rung Kao, Cheng-Wen Wu. YAP is an important pathway downstream of EGFR that is a potential target for EGFR-TKI-resistance lung adenocarcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2146.