A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Zhao Chen, Katherine Cheng, Zandra Walton, Yuchuan Wang, Hiromichi Ebi, Takeshi Shimamura, Yan Liu, Tanya Tupper, Jing Ouyang, Jie Li, Peng Gao, Michele S. Woo, Chunxiao Xu, Masahiko Yanagita, Abigail Altabef, Shumei Wang, Charles Lee, Yuji Nakada, Christopher G. Peña, Yanping Sun & 23 others Yoko Franchetti, Catherine Yao, Amy Saur, Michael D. Cameron, Mizuki Nishino, D. Neil Hayes, Matthew D. Wilkerson, Patrick J. Roberts, Carrie B. Lee, Nabeel Bardeesy, Mohit Butaney, Lucian R. Chirieac, Daniel B. Costa, David Jackman, Norman E. Sharpless, Diego H. Castrillon, George D. Demetri, Pasi A. Jänne, Pier Paolo Pandolfi, Lewis C. Cantley, Andrew L. Kung, Jeffrey A. Engelman, Kwok Kin Wong

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Abstract

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.

Original languageEnglish (US)
Pages (from-to)613-617
Number of pages5
JournalNature
Volume483
Issue number7391
DOIs
StatePublished - Mar 29 2012

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docetaxel
Lung Neoplasms
Clinical Trials
Mutation
Neoplasms
Biomarkers
Therapeutics
Mitogen-Activated Protein Kinase Kinases
Standard of Care
Genotype
Drug Therapy
AZD 6244

ASJC Scopus subject areas

  • General

Cite this

Chen, Z., Cheng, K., Walton, Z., Wang, Y., Ebi, H., Shimamura, T., ... Wong, K. K. (2012). A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature, 483(7391), 613-617. https://doi.org/10.1038/nature10937

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. / Chen, Zhao; Cheng, Katherine; Walton, Zandra; Wang, Yuchuan; Ebi, Hiromichi; Shimamura, Takeshi; Liu, Yan; Tupper, Tanya; Ouyang, Jing; Li, Jie; Gao, Peng; Woo, Michele S.; Xu, Chunxiao; Yanagita, Masahiko; Altabef, Abigail; Wang, Shumei; Lee, Charles; Nakada, Yuji; Peña, Christopher G.; Sun, Yanping; Franchetti, Yoko; Yao, Catherine; Saur, Amy; Cameron, Michael D.; Nishino, Mizuki; Hayes, D. Neil; Wilkerson, Matthew D.; Roberts, Patrick J.; Lee, Carrie B.; Bardeesy, Nabeel; Butaney, Mohit; Chirieac, Lucian R.; Costa, Daniel B.; Jackman, David; Sharpless, Norman E.; Castrillon, Diego H.; Demetri, George D.; Jänne, Pasi A.; Pandolfi, Pier Paolo; Cantley, Lewis C.; Kung, Andrew L.; Engelman, Jeffrey A.; Wong, Kwok Kin.

In: Nature, Vol. 483, No. 7391, 29.03.2012, p. 613-617.

Research output: Contribution to journalArticle

Chen, Z, Cheng, K, Walton, Z, Wang, Y, Ebi, H, Shimamura, T, Liu, Y, Tupper, T, Ouyang, J, Li, J, Gao, P, Woo, MS, Xu, C, Yanagita, M, Altabef, A, Wang, S, Lee, C, Nakada, Y, Peña, CG, Sun, Y, Franchetti, Y, Yao, C, Saur, A, Cameron, MD, Nishino, M, Hayes, DN, Wilkerson, MD, Roberts, PJ, Lee, CB, Bardeesy, N, Butaney, M, Chirieac, LR, Costa, DB, Jackman, D, Sharpless, NE, Castrillon, DH, Demetri, GD, Jänne, PA, Pandolfi, PP, Cantley, LC, Kung, AL, Engelman, JA & Wong, KK 2012, 'A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response', Nature, vol. 483, no. 7391, pp. 613-617. https://doi.org/10.1038/nature10937
Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature. 2012 Mar 29;483(7391):613-617. https://doi.org/10.1038/nature10937
Chen, Zhao ; Cheng, Katherine ; Walton, Zandra ; Wang, Yuchuan ; Ebi, Hiromichi ; Shimamura, Takeshi ; Liu, Yan ; Tupper, Tanya ; Ouyang, Jing ; Li, Jie ; Gao, Peng ; Woo, Michele S. ; Xu, Chunxiao ; Yanagita, Masahiko ; Altabef, Abigail ; Wang, Shumei ; Lee, Charles ; Nakada, Yuji ; Peña, Christopher G. ; Sun, Yanping ; Franchetti, Yoko ; Yao, Catherine ; Saur, Amy ; Cameron, Michael D. ; Nishino, Mizuki ; Hayes, D. Neil ; Wilkerson, Matthew D. ; Roberts, Patrick J. ; Lee, Carrie B. ; Bardeesy, Nabeel ; Butaney, Mohit ; Chirieac, Lucian R. ; Costa, Daniel B. ; Jackman, David ; Sharpless, Norman E. ; Castrillon, Diego H. ; Demetri, George D. ; Jänne, Pasi A. ; Pandolfi, Pier Paolo ; Cantley, Lewis C. ; Kung, Andrew L. ; Engelman, Jeffrey A. ; Wong, Kwok Kin. / A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. In: Nature. 2012 ; Vol. 483, No. 7391. pp. 613-617.
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abstract = "Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.",
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AU - Cheng, Katherine

AU - Walton, Zandra

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AU - Shimamura, Takeshi

AU - Liu, Yan

AU - Tupper, Tanya

AU - Ouyang, Jing

AU - Li, Jie

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AU - Woo, Michele S.

AU - Xu, Chunxiao

AU - Yanagita, Masahiko

AU - Altabef, Abigail

AU - Wang, Shumei

AU - Lee, Charles

AU - Nakada, Yuji

AU - Peña, Christopher G.

AU - Sun, Yanping

AU - Franchetti, Yoko

AU - Yao, Catherine

AU - Saur, Amy

AU - Cameron, Michael D.

AU - Nishino, Mizuki

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AU - Castrillon, Diego H.

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AU - Jänne, Pasi A.

AU - Pandolfi, Pier Paolo

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AU - Engelman, Jeffrey A.

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