新穎HDAC抑制劑對Gefitinib抗藥性之非小細胞肺癌幹細胞之研究

Abstract

目前針對表現過度活化epidermal growth factor receptor (EGFR) 之非小細胞肺癌治療主要是使用小分子藥物EGFR tyrosine kinase inhibitor (TKI)，如gefitinib 或是erlotinib。然而，因治療數月後對TKI產生抗藥性而導致腫瘤復發，稱為acquired resistance (secondary resistance)，已漸漸成為主要克服的議題。另外，因對傳統化療藥物產生抗藥性而提出癌幹細胞為主要造成癌症發生，維持和轉移，也成為是否造成對標把藥物譬如TKI產生抗藥性主因。本實驗中，發現非小細胞肺癌細胞株HCC827因長時間給與gefitinib後而形成癌細胞HCC827/IR，不但容易培養出癌幹細胞而且大量表現CD24low/CD44high和ALDH1A1。除此之外，這群癌幹細胞明顯表現epithelial mesenchymal transition (EMT)特徵且EMT影響癌幹細胞生成。因此尋找新一代藥物來對付此種抗藥性癌細胞是刻不容緩課題。除了化療和標把治療外，HDAC和HMG-CoA抑制劑也在癌症治療上占著舉足輕重的地位。我們研發出一種具有抑制HDAC 和HMG-CoA效果之抑制劑JMF3086，不但能有效降低肺癌細胞和肺癌幹細胞產生還能恢復此兩種細胞E-cadherin表現。因此，JMF3086為具潛能應用於對抗EGFR-TKI產生抗藥性之肺癌幹細胞。

Inhibition of EGFR tyrosine kinase by small molecule inhibitor, such as gefitinib or erlotinib, is an important treatment strategy for NSCLC with EGFR activating mutations. Currently, acquired resistance to EGFR TKI in NSCLC is becoming a critical problem to solve. Cancer stem cell (CSC) is a rare population in tumor to initiate tumor initiation, maintenance and metastasis, and confers resistance to chemotherapy. However, the role of CSC in TKI resistance needed investigation. We found that gefitinib acquired resistant NSCLC cell, HCC827/Iressa resistance (IR), had more CSC population, called spheroids with CD24low/CD44high feature and increased ALDH1A1 activity. Besides, these spheroids had strong epithelial mesenchymal transition (EMT) feature and EMT was related to their formation. Therefore, the aim of the present study was to find a new drug to overcome stemness-related EGFR TKI resistance. In addition to chemotherapy and targeted therapy, both of HDAC and HMG-CoA inhibition play vital role in cancer therapies. We generated a dual HDAC and HMG-CoA reductase (HMGR) inhibitor JMF3086 which inhibited HCC827/IR growth and its spheroid formation. Moreover, JMF3086 restored E-cadherin expression in HCC827/IR and its spheroid. Our results indicated that JMF3086 had a potential to overcome stemness-related EGFR TKI resistance.