title: A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.
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.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Katherine
authors.initials: K
authors.lastname: Cheng
authors.forename: Zandra
authors.initials: Z
authors.lastname: Walton
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tanya
authors.initials: T
authors.lastname: Tupper
authors.forename: Jing
authors.initials: J
authors.lastname: Ouyang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Michele S
authors.initials: MS
authors.lastname: Woo
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yanagita
authors.forename: Abigail
authors.initials: A
authors.lastname: Altabef
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakada
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Peña
authors.forename: Yanping
authors.initials: Y
authors.lastname: Sun
authors.forename: Yoko
authors.initials: Y
authors.lastname: Franchetti
authors.forename: Catherine
authors.initials: C
authors.lastname: Yao
authors.forename: Amy
authors.initials: A
authors.lastname: Saur
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishino
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: Carrie B
authors.initials: CB
authors.lastname: Lee
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: David
authors.initials: D
authors.lastname: Jackman
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D004195:Disease Models, Animal; D000077143:Docetaxel; D004353:Drug Evaluation, Preclinical; D019788:Fluorodeoxyglucose F18; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009154:Mutation / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D049268:Positron-Emission Tomography; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D043823:Taxoids / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D043823:Taxoids; D019788:Fluorodeoxyglucose F18; D000077143:Docetaxel; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins