EGFR-TKI已用于EGFR激活突变的非小细胞肺癌一线治疗，但仍有部分EGFR野生型患者接受EGFR-TKI治疗。我们前期证实，野生型肺癌细胞在EGFR-TKI持续暴露后导致多化疗药物抵抗，其机制为STAT3过度激活，这一耐药机制也存在于EGFR-TKI获得性耐药的EGFR突变细胞系，提示EGFR通路持续抑制后分子信号代偿具有共性。研究证实，STAT3激活与肿瘤转移、治疗抵抗及免疫逃逸密切相关，因此，STAT3过度激活的分子机制亟待阐明。我们前期证实TYK2可能为STAT3过度激活的上游分子，并有HSP90参与，本项目拟进一步研究TYK2/STAT3过度激活的分子机制及对肺癌细胞生物学行为的影响，并探讨分子干预策略。项目实施将有助深入理解EGFR-TKI持续暴露下肺癌的分子代偿机制，推动EGFR-TKI合理用药，并为EGFR-TKI耐药后后续治疗策略和新型分子靶向药物临床转化提供新思路。

EGFR-TKI has been used as first-line treatment for non-small cell lung cancer patients with EGFR activation mutations.However, there are still a part of patients with wild type EGFR were treated by EGFR-TKI. Our previous experiments confirmed that continuous EGFR - TKI exposure lead to multi chemotherapy drug resistance in EGFR wild type lung cancer cells. The underlying mechanism is the excessive activation of STAT3. The STAT3-mediated drug resistance phenomena are also observed in EGFR mutation cell line with EGFR-TKI acquired resistance, which reveal common molecular signal compensation follow by EGFR pathway continuous inhibition. Previous investigations have shown that STAT3 is a oncogene and its activation is closely related to tumor metastasis, treatment resistance and immune escape. Therefore, it is very important to clarify the molecular mechanism of excessive activation of STAT3 induced by EGFR-TKI. Our previous study suggested that TYK2 probably is a upstream molecule of STAT3 over-activation, and HSP90 may be involved. In current study, we will investigate the molecular mechanism of over-activation of TYK2/STAT3 and the influence on lung cancer biological behavior, what is more. Furthermore, molecular intervention strategy will also be investigated based on the results of molecular events. The implementation of this project will help understand the molecular compensatory mechanism response to EGFR-TKI continuous exposure in lung cancer, promote the rational use of EGFR-TKI, and provide more scientific treatment strategies followed by EGFR-TKI resistance and new insights for clinical translation of new molecular targeting drugs.