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SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo.
Nature Medicine ( IF 58.7 ) Pub Date : 2018-Jul-01 , DOI: 10.1038/s41591-018-0023-9
Sara Mainardi , Antonio Mulero-Sánchez , Anirudh Prahallad , Giovanni Germano , Astrid Bosma , Paul Krimpenfort , Cor Lieftink , Jeffrey D. Steinberg , Niels de Wit , Samuel Gonçalves-Ribeiro , Ernest Nadal , Alberto Bardelli , Alberto Villanueva , Rene Bernards

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.

中文翻译:

SHP2是体内KRAS突变非小细胞肺癌生长所必需的。

RAS突变在人类癌症中很常见,尤其是在胰腺癌,结肠直肠癌和非小细胞肺癌(NSCLCs)1-3中。RAS癌蛋白的抑制已被证明是困难的4,针对下游效应子5-7的尝试已被补偿性抗性机制的激活所阻碍8。还充分确定,KRAS突变肿瘤对上游生长因子受体信号传导的抑制不敏感。因此,表皮生长因子受体抗体治疗仅在KRAS野生型结肠癌9,10中有效。一致地,抑制SHP2(也称为PTPN11),它将受体酪氨酸激酶信号转导至RAS-RAF-MEK-ERK途径11,12,被证明在KRAS突变或BRAF突变的癌细胞系中无效13。我们的数据还表明,在正常细胞培养条件下,KRAS突变NSCLC细胞中SHP2的抑制作用很小。相比之下,在体外生长因子限制条件下对SHP2的抑制导致衰老反应。在体内,在KRAS突变型NSCLC中抑制SHP2也会引起衰老反应,而MEK抑制会加剧衰老反应。我们的数据将SHP2抑制识别为KRAS突变型NSCLC细胞的意外弱点,该弱点在细胞培养中仍未发现,可用于治疗。
更新日期:2018-05-29
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