KRas, in addition to Tp53 is a driver for early carcinogenesis and a molecular target in a mouse model of invasive gastro-esophageal adenocarcinoma

Abstract

Objective: The incidence of gastro-esophageal adenocarcinoma (GEAC) has increased dramatically and is associated with Barrett's Esophagus (BE). Gastric cardia progenitors are the likely origin for BE and GEAC. Here we analyze p53, Rb1 and Kras alterations in Lgr5 progenitor cells during carcinogenesis. Design: We introduced single and combined genetic alterations (p53, Rb1 and Kras) in Lgr5-expressing progenitor cells at the inflamed gastroesophageal junction in the L2-IL1b (L2) mouse model crossed to Lgr5-CreERT mice. For in-vitro treatment we utilized mouse and human 3D organoids. Results: Inactivation of Tp53 or Rb1 alone (L2-LP and L2-LR mice) resulted in metaplasia, and mild dysplasia, while expression of KrasG12D (L2-LK) accelerated dysplasia in L2-IL1b mice. Dual induction of genetic alteration in L2-LPR, L2-LKP and L2-LKR mice confirmed the accelerating role of mutant Kras, with the development of invasive cancer in mice with combined Tp53 and Kras alteration. All three genetic events in cardia progenitor cells generated invasive cancer at 6 months of age, with chromosomal instability (CNV). The dominant role of Kras prompted us to treat with a SHP2 inhibitor in combination with an ERK or MEK inhibitor, leading to reduced growth in Kras mutant organoids. SHP2 and MEK inhibition in-vivo reduced Kras-dependent tumor formation. Conclusion: In the first invasive GEAC mouse model, Kras mutation in combination with loss of tumor suppressor genes Tp53 or Rb1 emerges as a key player in GEAC and with the importance of p53 and Rb1 in promoting metaplasia. Targeting this SHP2/MEK/KRAS pathway represents a promising therapeutic option for Kras-altered GEAC.