An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants.
An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants.
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DOI：
10.1158/2159-8290.cd-20-0442
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发表时间：
2020-11
期刊：
影响因子：
28.2
通讯作者：
Dow LE
中科院分区：
文献类型：
--
作者：
Zafra MP;Parsons MJ;Kim J;Alonso-Curbelo D;Goswami S;Schatoff EM;Han T;Katti A;Fernandez MTC;Wilkinson JE;Piskounova E;Dow LE
KRAS是癌症中最常发生突变的癌基因，然而对于特异性KRAS氨基酸变化如何影响肿瘤的发生、进展或治疗反应，人们知之甚少。利用高保真crispr技术，我们创建了一系列新的LSL-Kras突变小鼠的等位基因，反映了在肺癌（KRASG12C）、胰腺癌（KRASG12R）和结肠癌（KRASG13D）中高度流行的密码子12和13突变。在小鼠结肠或胰腺中诱导每个等位基因，揭示了KRAS突变体在驱动转化早期阶段的显著定量和定性差异。此外，通过胰腺类器官模型，我们发现KRASG13D突变体对EGFR抑制敏感，而KRASG12C突变体类器官仅在EGFR被抑制时才对共价G12C抑制剂有选择性反应。总之，这些新的小鼠品系为研究体内KRAS生物学以及开发KRAS突变型胰腺癌、结肠癌和肺癌的临床前精确肿瘤学模型提供了理想的平台。
KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes impact tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R) and colon (KRASG13D) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Further, using pancreatic organoid models we show that KRASG13D mutants are sensitive to EGFR inhibition, while KRASG12C mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing pre-clinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers.