Abstract 1553: Carcinoembryonic antigen (CEA) expression is regulated by mutant KAS in mucinous colon cancers

Abstract

Abstract Purpose: Carcinoembryonic antigen (CEA/CEACAM5) is a marker and prognostic indicator for colorectal cancers (CRCs). CEA overexpression is also a major causative factor in the development of liver metastasis from a significant fraction of colorectal cancers (CRC) including mucinous adenocarcinomas (MCAs). Very little is known about the molecular mechanisms that regulate the expression of CEA in cancers in general and in CRCs in particular. This study tests the hypothesis that mutant KRAS, a frequently mutated gene in CRCs, regulates CEA expression in CRCs. Methods: Mutant KRAS expression was reduced in two high CEA-expressing mucinous CRC cell lines, LS174T (KRAS G12D) and RW7213 (KRAS G12C), by short hairpin RNA (shRNA)-mediated knockdown using a lentiviral vector. Inducible and reversible knockdown of KRAS was achieved by addition or withdrawal of doxycycline. Alterations in activation of ERK-and PI3K-pathway effectors downstream of KRAS were assessed by Western blots. Two small-molecule inhibitors, pictilisib (GDC0941) and cobimetinib (GDC0973), were used to inhibit PI3K and MEK respectively. Results: Knockdown of mutant KRAS in CRC cell lines reduced CEA expression. However, knockdown of wild-type RAS did not change CEA expression. Restoration of mutant KRAS reestablished CEA expression in both cell lines. This recovery of CEA expression was blocked by addition of the MEK inhibitor, cobimetinib or the PI3K inhibitor, picstilisib. Combined treatment with both inhibitors was more effective in reducing CEA expression than single-agent treatment. Conclusions: Our results suggest that mutant KRAS, through engagement of MEK-ERK and PI3K-AKT signaling pathways, regulates CEA expression in CRCs. CEA has been implicated in the development of lung and liver metastasis from CRCs, by reacting with stromal cells and altering the tumor microenvironment. Our results therefore, suggest a potential vulnerability that could be exploited for antimetastatic therapy. Citation Format: Murali Kuracha, Venkatesh Govindarajan, Brian W. Loggie, Peter Thomas. Carcinoembryonic antigen (CEA) expression is regulated by mutant KAS in mucinous colon cancers [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 1553.