Shin Sol-Bi, Kim Dae-Hoon, Kim Da-Eun, Aldonza Mark Borris D, Kim Yoosik, Yim Hyungshin
Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, Ansan 15588, Korea.
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Cancers (Basel). 2021 Sep 1;13(17):4413. doi: 10.3390/cancers13174413.
To overcome the limitations of chemoresistance, combination therapies using druggable targets have been investigated. Our previous studies led us to hypothesize that the downregulation of PLK1 expression or activity can be one strategy to overcome the hurdles of taxane resistance by the downregulation of ABC transporters. To explore this, various versions of PLK1 including a constitutively active version, kinase-dead form, and polo-box domain mutant were expressed in paclitaxel-resistant lung adenocarcinoma (LUAD). Targeting PLK1 using shRNA or non-functional mutants downregulated , , and in LUAD cells, which was similar to the downregulation effects from treatment with PLK1 inhibitors. The high expression of in LUAD led us to administer gefitinib, showing a markedly reduced level in LUAD cells. When gefitinib and PLK1 inhibitors were combined, LUAD cells tended to undergo apoptosis more effectively than parental cells, showing a synergistic effect on the downregulation of ABC transporters through c-Myc and AP-1. Clinical data provide evidence for the relevance between survival rates and expressions of and in LUAD patients. Based on these results, we suggest that a combination of gefitinib and PLK1 inhibitors exerts strong synergism in LUAD, which helps to overcome the limitations associated with taxanes.
为克服化疗耐药的局限性，人们对使用可成药靶点的联合疗法进行了研究。我们之前的研究使我们推测，下调PLK1的表达或活性可能是通过下调ABC转运蛋白来克服紫杉烷耐药障碍的一种策略。为了探究这一点，在耐紫杉醇的肺腺癌（LUAD）中表达了各种版本的PLK1，包括组成型活性版本、激酶失活形式和polo盒结构域突变体。使用shRNA或无功能突变体靶向PLK1可下调LUAD细胞中的 、 和 ，这与PLK1抑制剂处理的下调效果相似。LUAD中 的高表达促使我们给予吉非替尼，结果显示LUAD细胞中的 水平明显降低。当吉非替尼和PLK1抑制剂联合使用时，LUAD细胞比亲代细胞更倾向于更有效地发生凋亡，通过c-Myc和AP-1对ABC转运蛋白的下调显示出协同作用。临床数据为LUAD患者的生存率与 和 的表达之间的相关性提供了证据。基于这些结果，我们认为吉非替尼和PLK1抑制剂的联合在LUAD中发挥强大的协同作用，有助于克服与紫杉烷相关的局限性。
