COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.
复制标题
DOI：
10.1038/nature09627
复制
发表时间：
2010-12-16
期刊：
影响因子：
64.8
通讯作者：
Garraway, Levi A.
中科院分区：
文献类型：
--
作者：
Johannessen, Cory M.;Boehm, Jesse S.;Kim, So Young;Thomas, Sapana R.;Wardwell, Leslie;Johnson, Laura A.;Emery, Caroline M.;Stransky, Nicolas;Cogdill, Alexandria P.;Barretina, Jordi;Caponigro, Giordano;Hieronymus, Haley;Murray, Ryan R.;Salehi-Ashtiani, Kourosh;Hill, David E.;Vidal, Marc;Zhao, Jean J.;Yang, Xiaoping;Alkan, Ozan;Kim, Sungjoon;Harris, Jennifer L.;Wilson, Christopher J.;Myer, Vic E.;Finan, Peter M.;Root, David E.;Roberts, Thomas M.;Golub, Todd;Flaherty, Keith T.;Dummer, Reinhard;Weber, Barbara L.;Sellers, William R.;Schlegel, Robert;Wargo, Jennifer A.;Hahn, William C.;Garraway, Levi A.
在50-70%的恶性黑色素瘤中发现了丝氨酸/苏氨酸激酶B-RAF的致癌突变。临床前研究表明，B-RAFV600E突变预示着黑色素瘤对丝裂原活化蛋白激酶(MAPK)信号级联的依赖性-这一观察结果已被RAF和MEK抑制剂在临床试验中的成功验证。然而，靶向抗癌治疗的临床反应经常被从头开始或获得性耐药所混淆。以阐明可替代的“可用药”靶点的方式识别耐药机制可能为有效的长期治疗策略提供依据。在这里，我们平行表达了~600个激酶和激酶相关的开放阅读框架(ORF)，以从功能上询问对选择性RAF激酶抑制剂的抗性。我们发现MAP3K8(CoT/Tpl2)是一种MAPK途径激动剂，可以在B-RAFV600E细胞株中驱动对RAF抑制的抵抗。COT主要通过不需要RAF信号的MEK依赖机制激活ERK。此外，COT的表达与B-RAFV600E培养细胞系的从头耐药以及黑色素瘤细胞和复发患者经MEK或RAF抑制治疗后获得的获得性耐药有关。我们进一步确定，在这种情况下，联合抑制MAPK通路或靶向CoT激酶活性是减少MAPK通路激活的可能的治疗策略。总之，这些结果为涉及MAPK通路的耐药机制提供了新的见解，并阐明了一种综合方法，通过高通量功能筛选可以为新治疗策略的开发提供信息。
Oncogenic mutations in the serine/threonine kinase B-RAF are found in 50–70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAFV600E mutation predicts a dependency on the mitogen activated protein kinase (MAPK) signaling cascade in melanoma—an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative ‘druggable’ targets may inform effective long-term treatment strategies. Here, we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to functionally interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (COT/TPL2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAFV600E cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in B-RAFV600E cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibition. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
登录
查看更多内容
影响因子：
11.2
作者：
Lee KM;Lee KW;Bode AM;Lee HJ;Dong Z
通讯作者：
Dong Z
影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
16
作者：
Karreth, Florian A.;DeNicola, Gina M.;Tuveson, David A.
通讯作者：
Tuveson, David A.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
24.5
作者：
Seth, R.;Crook, S.;Ilyas, M.
通讯作者：
Ilyas, M.