Abstract A24: New mouse models with KRASG12D or KRASG12V mutation in Amhr2-Cre mice develop different gynecologic tumors
Authors: Wong Kwong-Kwok , Tsang Yvonne T. , Bao Wei , Lin Sophia , Kun Eucharist , Ren Yi A. , Richards JoAnne S. , Gershenson David M. 
Published: June 2021

Abstract
Low-grade ovarian serous carcinoma (LGSC) accounts for a relatively large percentage of epithelial ovarian cancers in young women, and approximately 30% of LGSC carries a KRAS mutation. Chemotherapy and hormonal therapy are relatively ineffective and have generally failed to reduce high morbidity and mortality. Importantly, although LGSC is considered to be an indolent cancer, with an estimated median overall survival of 80 months, an updated analysis of 350 women with LGSC from our Low-Grade Serous Tumor Database indicated that over 85% developed recurrent disease, and almost all ultimately died of the disease. The overall response rate of recurrent LGSC to various chemotherapy drugs is dismal—less than 4%. Our previous study by correlating the KRAS mutation status of 503 cancer cell lines and their sensitivity to MEK inhibitor from the Cancer Cell Line Encyclopedia (CCLE) database suggests that KRASG12V-mutated cell line might be more sensitive to MEK inhibitor selumetinib. In addition, we found that patients with ovarian serous borderline tumor that progressed as LGSC with KRASG12V mutation appear to have shorter survival than that with KRASG12D mutation or wild-type gene. To address whether tumors initiated with KRASG12D or KRASG12V have any difference on tumor initiation and drug response, we have generated two mouse models with conditionally expressed KRASG12DS(+/-) or KRASG12V mutation using Amhr2-Cre mice. The Amhr2-Cre mice express Cre recombinase in tissues that develop into the fallopian tubes, uterus and ovary. In this presentation, we will describe the differences in the gynecologic tumors formed by these mice. Mice with the genotype of Ahmr2-Cre Pten(-/-) KRASG12D/+ had abnormal follicle structure and developed low-grade ovarian serous carcinomas with 100 penetrance within 18 weeks. Surprisingly, mice with the genotype of Ahmr2-Cre Pten(-/-) KRASG12V/+ had normal follicle structure but developed uterine tumors with diverse histology resembling that of leiomyoma, and leiomyosarcoma. Some mice even developed uterine tumors with leiomyoma region, leiomyosarcoma-like region as well as low-grade carcinoma. Multinodular and highly vascular leiomyosarcoma was also observed in some of these mice. Therefore, these models will be useful for studying the difference in signaling pathways driven by KRASG12D or KRASG12V mutation for developing targeted therapies for specific KRAS mutant variants. Currently, we are investigating whether KRASG12D or KRASG12V mutation has any impact on the estrogen receptor pathway in the uterine tissue. The leiomyoma model driven by KRASG12V mutation in this study will also be useful to decipher the malignant progression of leiomyoma to leiomyosarcoma.
Citation Format: Kwong-Kwok Wong, Yvonne T. Tsang, Wei Bao, Sophia Lin, Eucharist Kun, Yi A. Ren, JoAnne S. Richards, David M. Gershenson. New mouse models with KRASG12D or KRASG12V mutation in Amhr2-Cre mice develop different gynecologic tumors [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A24.