Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models.
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.
Singh
Mallika
M
Department of Molecular Biology, Genentech, Inc., South San Francisco, California, USA. msingh@gene.com
Lima
Anthony
A
Molina
Rafael
R
Hamilton
Patricia
P
Clermont
Anne C
AC
Devasthali
Vidusha
V
Thompson
Jennifer D
JD
Cheng
Jason H
JH
Bou Reslan
Hani
H
Ho
Calvin C K
CC
Cao
Timothy C
TC
Lee
Chingwei V
CV
Nannini
Michelle A
MA
Fuh
Germaine
G
Carano
Richard A D
RA
Koeppen
Hartmut
H
Yu
Ron X
RX
Forrest
William F
WF
Plowman
Gregory D
GD
Johnson
Leisa
L
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D000069347:Erlotinib Hydrochloride; D005818:Genetic Engineering; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011799:Quinazolines / Q000627:therapeutic use; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D000093542:Gemcitabine
D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine