Wu Kai, Chang Qingshan, Lu Yongju, Qiu Ping, Chen Bailing, Thakur Chitra, Sun Jiaying, Li Lingzhi, Kowluru Anjaneyulu, Chen Fei
Oncotarget. 2013 Dec;4(12):2430-8. doi: 10.18632/oncotarget.1431.
Hyperactivation of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase is prevalent in human lung cancer and its inhibition by the tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, initially controls tumor growth. However, most patients ultimately relapse due to the development of drug resistance. In this study, we have discovered a STAT3-dependent Akt activation that impairs the efficacy of gefitinib. Mechanistically, gefitinib increased association of EGFR with STAT3, which de-repressed STAT3 from SOCS3, an upstream suppressor of STAT3. Such a de-repression of STAT3 in turn fostered Akt activation. Genetic or pharmacological inhibition of STAT3 abrogated Akt activation and combined gefitinib with STAT3 inhibition synergistically reduced the growth of the tumor cells. Taken together, this study suggests that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFR TKIs. Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs in lung cancer.
表皮生长因子受体（EGFR）酪氨酸激酶的过度激活在人类肺癌中普遍存在，酪氨酸激酶抑制剂（TKIs），包括吉非替尼和厄洛替尼，对其抑制作用最初可控制肿瘤生长。然而，大多数患者最终会因耐药性的产生而复发。在本研究中，我们发现了一种依赖STAT3的Akt激活，它损害了吉非替尼的疗效。从机制上讲，吉非替尼增加了EGFR与STAT3的结合，从而使STAT3从其上游抑制因子SOCS3的抑制中解脱出来。STAT3的这种解脱反过来又促进了Akt的激活。对STAT3进行基因或药理学抑制可消除Akt的激活，将吉非替尼与STAT3抑制联合使用可协同降低肿瘤细胞的生长。综上所述，本研究表明STAT3的激活是对EGFR TKIs产生耐药性的一种内在机制。同时靶向EGFR和STAT3可能会增强吉非替尼或其他EGFR TKIs在肺癌治疗中的疗效。
