Khatri Aaditya, Gu Jing Jin, McKernan Courtney M, Xu Xia, Pendergast Ann Marie
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
Oncotarget. 2019 Mar 8;10(20):1874-1886. doi: 10.18632/oncotarget.26740.
Lung cancer is the leading cause of cancer mortality in the United States, with an overall five-year survival rate of ~16%. Non-small cell lung cancer (NSCLC) accounts for ~80% of all lung cancer cases, and the majority (40%) of these are adenocarcinomas. Loss of function point mutations in (46%) and activating mutations in (33%) are the most common mutations in human lung adenocarcinomas. Because neither of these genetic alterations are clinically actionable, chemotherapy remains the mainstay of treatment in patients with oncogenic driver mutations. However, chemoresistance to genotoxic agents such as docetaxel remains a major clinical challenge facing lung cancer patients. Here we show that ABL kinase allosteric inhibitors can be effectively used for the treatment of lung adenocarcinomas in an autochthonous mouse model. Unexpectedly, we found that treatment of tumor-bearing mice with an ABL allosteric inhibitor promoted differentiation of lung adenocarcinomas from poorly differentiated tumors expressing basal cell markers to tumors expressing terminal differentiation markers , which rendered lung adenocarcinomas susceptible to chemotherapy. These findings uncover a novel therapeutic approach for the treatment of lung adenocarcinomas with poor response to chemotherapy.
肺癌是美国癌症死亡的主要原因，总体五年生存率约为16%。非小细胞肺癌（NSCLC）占所有肺癌病例的约80%，其中大多数（40%）为腺癌。（46%）的功能丧失点突变和（33%）的激活突变是人类肺腺癌中最常见的突变。由于这些基因改变在临床上均不可操作，化疗仍然是具有致癌驱动突变患者的主要治疗方法。然而，对多西他赛等基因毒性药物的化疗耐药仍然是肺癌患者面临的主要临床挑战。在此，我们表明ABL激酶变构抑制剂可有效用于在同种异体小鼠模型中治疗肺腺癌。出乎意料的是，我们发现用ABL变构抑制剂治疗荷瘤小鼠可促进肺腺癌从不表达终末分化标志物的低分化肿瘤表达基底细胞标志物向表达终末分化标志物的肿瘤分化，这使得肺腺癌对化疗敏感。这些发现揭示了一种治疗对化疗反应不佳的肺腺癌的新治疗方法。
