Abstract
The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance.
Highlights
IntroductionWhereas cancer cell lines have been integral to the development of most anti-cancer drugs and exhibit genotype-specific responses to some targeted inhibitors, they fail to model many fundamental properties of primary tumors
Most new anti-cancer agents fail in the clinic [1]
We comprehensively profiled a panel of primary mouse T lineage leukemias initiated by insertional mutagenesis and found remarkable similarities with human T lineage acute lymphoblastic leukemias (T-ALLs) in regard to overall mutational burden, the occurrence of specific somatic mutations and large chromosomal alterations, and concordant gene expression signatures
Summary
Whereas cancer cell lines have been integral to the development of most anti-cancer drugs and exhibit genotype-specific responses to some targeted inhibitors, they fail to model many fundamental properties of primary tumors. Mouse models in which cancers arise due to mutations introduced into the germline or following exposure to chemical mutagens have distinct advantages and liabilities. Engineered mouse (GEM) models reproduce many morphologic features of advanced human cancers, but diverge substantially with respect to the overall mutational burden and pattern of copy number alterations [4,5,6,7,8]. Whereas models initiated by chemical carcinogens may more accurately reflect the mutational profile of some human cancers [4, 6], extensive genetic variability and the inability to perform technical replicates are substantial barriers to widespread preclinical use
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