McCubrey James A, Steelman Linda S, Chappell William H, Abrams Stephen L, Montalto Giuseppe, Cervello Melchiorre, Nicoletti Ferdinando, Fagone Paolo, Malaponte Grazia, Mazzarino Maria C, Candido Saverio, Libra Massimo, Bäsecke Jörg, Mijatovic Sanja, Maksimovic-Ivanic Danijela, Milella Michele, Tafuri Agostino, Cocco Lucio, Evangelisti Camilla, Chiarini Francesca, Martelli Alberto M
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
Oncotarget. 2012 Sep;3(9):954-87. doi: 10.18632/oncotarget.652.
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.
Ras/Raf/MEK/ERK和PI3K/PTEN/Akt/mTOR级联反应通常由上游信号分子（如受体酪氨酸激酶，RTK）的基因改变所激活。这些信号通路的某些组分，如RAS、NF1、BRAF、MEK1、DUSP5、PP2A、PIK3CA、PIK3R1、PIK3R4、PIK3R5、IRS4、AKT、NFKB1、MTOR、PTEN、TSC1和TSC2，也可能因突变或表观遗传沉默而被激活/失活。一条信号通路中的上游突变，甚至同一通路下游组分的突变，都可能改变细胞对某些小分子抑制剂的敏感性。这些信号通路对增殖、凋亡和分化通路具有深远影响。这些级联反应组分的失调可能导致：对其他通路抑制剂产生耐药性、对化疗药物产生耐药性、早衰以及引发其他疾病。本综述将首先描述这些信号通路，并讨论基因突变和表观遗传改变如何导致对各种抑制剂产生耐药性。
