Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cell Rep. 2021 Jun 29;35(13):109291. doi: 10.1016/j.celrep.2021.109291.
To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the βIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.
为了确定 KRAS 突变型胰腺癌细胞的治疗靶点，我们进行了可成药基因组小干扰 RNA (siRNA) 筛选，结果表明抑制 BCAR1 可使胰腺癌细胞对 ERK 抑制敏感。对基因组规模的 CRISPR-Cas9 筛选的综合分析也确定 BCAR1 是与突变型 KRAS 具有最高合成致死相互作用的基因。BCAR1 编码 SRC 底物 p130Cas。我们确定 SRC 抑制剂介导的 p130Cas 磷酸化抑制通过 DOCK1-RAC1-β-catenin 依赖性机制损害 MYC 转录。此外，微管 βIII 微管蛋白亚单位编码基因 TUBB3 的遗传抑制或微管功能的药理学抑制以钙蛋白酶依赖性方式降低 MYC 蛋白水平，并强烈使胰腺癌细胞对 ERK 抑制敏感。因此，双重 SRC/微管抑制剂与 ERK 抑制剂的联合使用可协同减少 MYC 蛋白并协同抑制 KRAS 突变型胰腺癌细胞的生长。因此，我们证明了与 ERK 抑制联合使用具有不同作用机制的组合可抑制 MYC 以损害胰腺癌细胞的增殖。
