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

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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.

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Figure 1: Influence of KRAS mutations in the first-line treatment of NSCLC with chemotherapy versus chemotherapy plus erlotinib.
Figure 2: First-line treatment of PDAC patients and KrasLSL−G12D; p16/p19fl/fl; Pdx1-Cre mice with gemcitabine versus gemcitabine plus erlotinib.
Figure 3: Anti-VEGF provides significant benefit when combined with chemotherapy as first-line therapy in human patients and KrasLSL−G12D; p53frt/frt mice with late-stage NSCLC.
Figure 4: First-line treatment of PDAC patients and KrasLSL−G12D; p16/p19fl/fl; Pdx1-Cre mice with gemcitabine versus gemcitabine plus anti-VEGF.
Figure 5: Anti-VEGF is a primary driver of response in the Kras mutant NSCLC GEMM.
Figure 6: Gemcitabine is a primary driver of a survival benefit, with incremental benefit conferred by the addition of targeted agents in a Kras mutant PDAC GEMM.


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We would like to thank S. Kelsey, J. Hambleton, O. Rosen, S. Erickson, F. Borellini, D. Colburn and G. Evan for critically evaluating the manuscript as well as F. de Sauvage, B. Mass and M. Benyunes for invaluable input. J. Bower, V. Javinal, A. Arrazate, L. Nguyen and A. Wong provided excellent technical assistance. We also received extensive and able technical support from the in-house genotyping and murine reproductive technology core groups. A special note of gratitude to H. Wong, L. Salphati, B. Liederer and L. Damico for pharmacokinetic support and analyses. L. Berry and B. Hollister supervised the xenograft studies shown here. B. Tong, J. Yi and J. Wacker provided statistical information and feedback. The graphics and layout were ably provided by J. Wood and D. Wood.

Author information

M.S. and L.J. designed, planned and performed the experiments, analyzed data and wrote the manuscript. A.L., R.M., P.H., A.C.C., V.D., J.D.T., J.H.C., H.B.R., C.C.K.H. and T.C.C. performed experiments and analyzed data. C.V.L. and G.F. developed and provided the B20-4.1.1 anti-VEGF antibody. M.A.N. and R.A.D.C. provided design input and supervised animal dosing and imaging experiments, respectively. G.D.P. provided design input and contributed to manuscript preparation. H.K. carried out histopathological analyses, and R.X.Y. and W.F.F. performed all the statistical analyses and contributed to the writing of the manuscript.

Correspondence to Mallika Singh or Leisa Johnson.

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The authors are current or past employees of Genentech, Inc. and/or may have stocks or shares in Roche, Inc.

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Singh, M., Lima, A., Molina, R. et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol 28, 585–593 (2010) doi:10.1038/nbt.1640

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