拉帕替尼(lapatinib)是一種表皮生長因子受體和第二型表皮生長因子受體的雙重小分子酪胺酸抑制劑，在臨床上用於治療第二型表皮生長因子受體陽性的乳癌病人。臨床上發現三陰性乳癌病患雖有表皮生長因子受體蛋白的表現，但給予拉帕替尼治療效果卻不彰，其中原因尚未釐清。在本研究中我們意外發現這樣的治療不僅無效反而造成癌細胞轉移。結果顯示長期給予拉帕替尼會誘導介白素-6大量表現，加劇癌細胞爬行與侵入;其中拉帕替尼可以藉由增加Raf-1/MAPK/AP-1路徑的活性來提高介白素-6的表現。更進一步的結果顯示，拉帕替尼抑制表皮生長因子受體酪胺酸激?活性而降低細胞內小片段核糖核酸-7的表現量;由於小片段核糖核酸-7可直接結合在Raf-1 3’UTR而抑制其蛋白的表現，因此拉帕替尼可經由降低小片段核糖核酸-7來提高Raf-1的蛋白量及下游MAPK/AP-1 路徑，最後達到增加介白素-6基因轉錄的作用。因此，本論文研究發現拉帕替尼經由小片段核糖核酸-7/Raf-1/MAPK/AP-1的訊號路徑，增加介白素-6大量表現而導致三陰性癌細胞轉移。由於第二型表皮生長因子受體陽性腫瘤中仍存在有相當比例的表皮生長因子受體-2陰性癌細胞;因此，我們的發現建議在臨床上以拉帕替尼治療時，必須考慮第二型表皮生長因子受體的異質表現性，避免拉帕替尼作用在第二型表皮生長因子受體陰性細胞而促進轉移，同時或許也可透過抑制介白素-6的表現，提高拉帕替尼的治療效果。
Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3’UTR activity, and that down-regulation of microRNA-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of microRNA-7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.
