Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models

Abstract

The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs--one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma--by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance.

Establishment of an orthotopic pancreatic cancer mouse model: Cells suspended and injected in Matrigel

“…Current animal models of pancreatic cancer include xenograft models [7][8][9] , carcinogen-induced models [10][11][12][13] , and genetically engineered models [14][15][16][17][18] . In the carcinogeninduced model, when pancreatic cancer is induced, hepatocellular carcinoma and other tumors occur simultaneously due to poor specificity of the carcinogen; thereby, the accuracy of using such animal models is limited.…”

Molecular pathology of lung cancer: key to personalized medicine

“…The ligand binding-induced dimerization results in cross-autophosphorylation of key tyrosine residues in the cytoplasmic domains, which function as docking sites for downstream signal transducers. 36 This activation of EGFR initiates signaling cascades involving several downstream pathways, which induce crucial cellular responses, such as proliferation, differentiation, motility, and survival 13,[52][53][54][55][56][57][58][59][60][61][62] (Figure 1).…”

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

“…1). The importance of these mutations is highlighted by the development of genetically engineered mouse models that harbor KRAS and p53 mutations and are able to drive lung adenocarcinoma initiation and progression (2). In recent years, molecular and cancer genomic approaches have increased our understanding of the pathogenesis of NSCLC and have led to therapies that directly target the precise genetic alterations that drive tumor growth.…”