PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs
PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs
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DOI：
10.1016/j.celrep.2015.08.037
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发表时间：
2015-09-29
期刊：
影响因子：
8.8
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
--
作者：
Prahallad, Anirudh;Heynen, Guus J. J. E.;Bernards, Rene
大多数BRAF(V600E)突变黑色素瘤对选择性BRAF抑制剂敏感，但由于EGFR的反馈激活，BRAF突变结肠癌对这些药物具有内在耐药性。我们在BRAF突变的结肠癌细胞中进行了基于RNA干扰的遗传筛选，以寻找其基因敲除导致对BRAF抑制的敏感性的磷酸酶。我们发现，抑制蛋白酪氨酸磷酸酶非受体11(PTPN11)在结肠癌中增加了对BRAF抑制剂的敏感性。从机制上讲，我们发现抑制PTPN11可以阻断从受体酪氨酸激酶(RTK)到Ras-MEK-ERK通路的信号传导。PTPN11抑制对由激活的RTK驱动的细胞是致命的，并防止由于RTK激活而导致的对靶向癌症药物的获得性耐药性。我们的发现将PTPN11确定为一个药物靶点，以对抗几种靶向抗癌药物的内在和获得性耐药性。此外，激活的PTPN11可以作为RTK激活引起的耐药的生物标志物。
Most BRAF (V600E) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition. We found that suppression of protein tyrosine phosphatase non-receptor type 11 (PTPN11) confers sensitivity to BRAF inhibitors in colon cancer. Mechanistically, we found that inhibition of PTPN11 blocks signaling from receptor tyrosine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation. Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Moreover, activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation.