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Novel Kras-mutant murine models of non-small cell lung cancer possessing co-occurring oncogenic mutations and increased tumor mutational burden

View ORCID ProfileRamin Salehi-Rad, View ORCID ProfileRui Li, View ORCID ProfileLinh M. Tran, View ORCID ProfileRaymond J. Lim, Jensen Abascal, Milica Momcilovic, Stacy J. Park, Stephanie L. Ong, Zi Ling Huang, View ORCID ProfileManash Paul, View ORCID ProfileDavid B. Shackelford, View ORCID ProfileKostyantyn Krysan, View ORCID ProfileBin Liu, Steven M. Dubinett
doi: https://doi.org/10.1101/2020.02.15.950220
Ramin Salehi-Rad
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
2Department of Medicine, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
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Rui Li
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Linh M. Tran
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Raymond J. Lim
3Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
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Jensen Abascal
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Milica Momcilovic
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Stacy J. Park
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Stephanie L. Ong
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Zi Ling Huang
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Manash Paul
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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David B. Shackelford
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
3Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
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Kostyantyn Krysan
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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Bin Liu
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
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  • For correspondence: bliu@mednet.ucla.edu sdubinett@mednet.ucla.edu
Steven M. Dubinett
1Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90025-1690, USA
2Department of Medicine, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
3Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
4Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Los Angeles, CA 90095, USA
5Jonsson Comprehensive Cancer Center, UCLA, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781, USA
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  • For correspondence: bliu@mednet.ucla.edu sdubinett@mednet.ucla.edu
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Abstract

Despite recent advances in lung cancer immunotherapy, a major obstacle to the progress in the field is the lack of preclinical models that recapitulate the genetic and immunologic complexity of human disease. Conditional genetically engineered mouse models (GEMMs) of non-small cell lung cancer (NSCLC) harbor the common oncogenic mutations of the disease, but these models possess low tumor mutational burden (TMB), which limits their utility in immunotherapy studies. Here, we establish novel Kras-mutant murine models of NSCLC bearing common genetic alterations associated with the disease and increased TMB, by in vitro exposure of cell lines derived from GEMMs of NSCLC [KrasG12D (K), KrasG12DTp53−/− (KP), KrasG12DTp53+/−Lkb1−/− (KPL)] to the alkylating agent N-methyl-N-nitrosourea (MNU). Increased TMB was associated with enhanced anti-tumor T cell responses and improved anti-PD-1 efficacy in syngeneic models, across all genetic backgrounds. However, anti-PD-1 efficacy was comparatively modest in the KPL cell lines with increased TMB, which possessed a distinct immunosuppressed tumor microenvironment (TME) primarily composed of granulocytic myeloid-derived suppressor cells (G-MDSCs). This phenotype is consistent with findings in human NSCLC where LKB1 loss is a driver of primary resistance to PD-1 blockade. In summary, these novel Kras-mutant murine NSCLC models bearing common co-occurring mutations with increased TMB possess clinically relevant TMEs and recapitulate the genetic complexity and therapeutic vulnerabilities of human NSCLC. We anticipate that these immunogenic models will facilitate the development of novel immunotherapies in NSCLC.

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Posted February 16, 2020.
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Novel Kras-mutant murine models of non-small cell lung cancer possessing co-occurring oncogenic mutations and increased tumor mutational burden
Ramin Salehi-Rad, Rui Li, Linh M. Tran, Raymond J. Lim, Jensen Abascal, Milica Momcilovic, Stacy J. Park, Stephanie L. Ong, Zi Ling Huang, Manash Paul, David B. Shackelford, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett
bioRxiv 2020.02.15.950220; doi: https://doi.org/10.1101/2020.02.15.950220
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Novel Kras-mutant murine models of non-small cell lung cancer possessing co-occurring oncogenic mutations and increased tumor mutational burden
Ramin Salehi-Rad, Rui Li, Linh M. Tran, Raymond J. Lim, Jensen Abascal, Milica Momcilovic, Stacy J. Park, Stephanie L. Ong, Zi Ling Huang, Manash Paul, David B. Shackelford, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett
bioRxiv 2020.02.15.950220; doi: https://doi.org/10.1101/2020.02.15.950220

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