a Department of Pharmacy, Anhui No.2 Provincial People's Hospital , Hefei , China.
b Research Department, The First Affiliated Hospital of USTC , Hefei , China.
Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):3231-3238. doi: 10.1080/21691401.2019.1646748.
RAS mutations are frequent in non-small cell lung cancer (NSCLC). However, targeting RAS or the downstream/upstream effectors, such as tyrosine kinase inhibitors (TKIs), has been proved to be difficult. Here, we found that the stemness of KRAS-mutant NSCLC cells but not the KRAS-wild type NSCLC cells was promoted by TKIs treatment, as evident by the increase of ALDH1 activity, stemness marker expression and spheroid formation ability. Notably, SHP2 activation was found in KRAS-mutant NSCLC cells with TKIs treatment, as judged by the increase of tyrosine 542 phosphorylation (pSHP2 Y542), which activates the RAS/MEK/ERK pathway. On the contrary, inhibition of MEK was followed by a SHP2 activation in KRAS-mutant NSCLC cells. Additionally, inhibition of SHP2 attenuates the enhanced stemness of KRAS-mutant NSCLC cells induced by TKIs, characterized by decreasing ALDH1 activity, stemness marker expression and spheroid formation capacity, while had little effects on cell viability. Finally, we revealed that SHP2 inhibitor increased the sensitivity of TKIs and chemotherapy, which was potentiated by MEK inhibition. Our results suggest a possibility of using a combination of SHP2 inhibitor and TKIs for KRAS-mutant NSCLC treatment.
RAS 突变在非小细胞肺癌（NSCLC）中很常见。然而，靶向 RAS 或下游/上游效应物，如酪氨酸激酶抑制剂（TKIs），已被证明是困难的。在这里，我们发现 KRAS 突变型 NSCLC 细胞的干性而不是 KRAS 野生型 NSCLC 细胞的干性被 TKI 治疗促进，这表现在 ALDH1 活性、干性标志物表达和球体形成能力的增加。值得注意的是，在 KRAS 突变型 NSCLC 细胞中发现了 SHP2 的激活，这可以通过酪氨酸 542 磷酸化（pSHP2 Y542）的增加来判断，从而激活 RAS/MEK/ERK 通路。相反，在 KRAS 突变型 NSCLC 细胞中抑制 MEK 后会导致 SHP2 的激活。此外，抑制 SHP2 可减弱 TKI 诱导的 KRAS 突变型 NSCLC 细胞增强的干性，表现为 ALDH1 活性、干性标志物表达和球体形成能力降低，而对细胞活力影响不大。最后，我们揭示了 SHP2 抑制剂增加了 TKIs 和化疗的敏感性，并且这种敏感性通过 MEK 抑制得到增强。我们的结果表明，使用 SHP2 抑制剂和 TKI 联合治疗 KRAS 突变型 NSCLC 的可能性。
