DataSheet_1_Platelet Activation in High D-Dimer Plasma Plays a Role in Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Mutant Lung Adenocarcinoma.docx

ObjectivePlatelet activation and adhesion to cancer cells increase the release of multiple factors that contribute to EMT and chemoresistance. Elevated levels of D-dimer have been associated with poor clinical outcomes in lung cancer. Platelets in high D-dimer plasma may be activated and implicated in acquired resistance to EGFR TKI in advanced lung adenocarcinoma with mutant EGFR.
Materials and MethodsClinical responsive rate (RR), progression-free survival (PFS), and overall survival (OS) were prospectively measured in treatment-naïve lung adenocarcinoma patients with activation mutation. Plasma or platelets from patients with high or low D-dimer level were obtained to investigate the cytotoxic effects of TKIs on mutant cancer cells, and the mechanistic pathways were also explored.
ResultsPatients with high D-dimer had worse RR, PFS, and OS. High D-dimer plasma induced resistance to gefitinib, erlotinib, afatinib, or osimertinib in EGFR mutant lung cancer cells. Depletion of platelets in high D-dimer plasma reversed the resistance to TKI. Platelets of high D-dimer plasma had higher adherence capacity to cancer cells, and induced EGFR and Akt activation as well as EMT through Src activation. Inhibition of platelet adherence or activation of Src or Akt conquered the resistance to TKI. The acquired resistance to TKI by high D-dimer plasma was less attributed to secondary gene mutation.
ConclusionIncreased platelet activation in the high D-dimer plasma may contribute to first-line acquired EGFR TKI resistance. Thus, therapeutic strategy against platelet activation in patients with high D-dimer levels may improve the efficacy of first-line treatment with EGFR TKI.

研究目的：血小板活化并黏附于癌细胞后，可促进多种促上皮间质转化（epithelial-mesenchymal transition, EMT）及化疗耐药相关因子的释放。血浆D-二聚体水平升高与肺癌患者不良临床预后相关。在携带EGFR致敏突变的晚期肺腺癌患者中，高D-二聚体血浆内的血小板可能被活化，并参与表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKI）获得性耐药的发生。
材料与方法：本研究前瞻性纳入初治EGFR致敏突变型肺腺癌患者，前瞻性测定其临床缓解率（responsive rate, RR）、无进展生存期（progression-free survival, PFS）及总生存期（overall survival, OS）。采集高、低D-二聚体水平患者的血浆或血小板，以探讨酪氨酸激酶抑制剂（TKIs）对突变癌细胞的细胞毒性作用，并深入探究其潜在分子机制。
研究结果：高D-二聚体水平患者的临床缓解率、无进展生存期及总生存期均更差。高D-二聚体血浆可诱导EGFR突变型肺腺癌细胞对吉非替尼、厄洛替尼、阿法替尼及奥希替尼产生耐药性。去除高D-二聚体血浆中的血小板后，可逆转其对酪氨酸激酶抑制剂的耐药性。高D-二聚体血浆中的血小板对癌细胞的黏附能力更强，可通过激活Src通路诱导EGFR、Akt活化及上皮间质转化（EMT）。抑制血小板黏附或激活Src、Akt通路，可克服该酪氨酸激酶抑制剂耐药性。此外，高D-二聚体血浆诱导的酪氨酸激酶抑制剂获得性耐药，较少由继发基因突变导致。
研究结论：高D-二聚体血浆中增强的血小板活化，可能是一线EGFR TKI获得性耐药的潜在诱因。因此，针对高D-二聚体患者的血小板活化进行干预的治疗策略，或可提升EGFR TKI一线治疗的临床疗效。