Wilson Frederick H, Johannessen Cory M, Piccioni Federica, Tamayo Pablo, Kim Jong Wook, Van Allen Eliezer M, Corsello Steven M, Capelletti Marzia, Calles Antonio, Butaney Mohit, Sharifnia Tanaz, Gabriel Stacey B, Mesirov Jill P, Hahn William C, Engelman Jeffrey A, Meyerson Matthew, Root David E, Jänne Pasi A, Garraway Levi A
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cancer Cell. 2015 Mar 9;27(3):397-408. doi: 10.1016/j.ccell.2015.02.005.
We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.
我们开展了一项大规模功能遗传学研究，以阐明ALK依赖型肺癌细胞对ALK抑制产生抗性的机制。我们鉴定出已知抗性途径的成员以及其他潜在的抗性驱动因素。后者包括G蛋白偶联受体的P2Y嘌呤能受体家族成员（P2Y1、P2Y2和P2Y6）。P2Y受体部分通过蛋白激酶C（PKC）依赖机制介导抗性。此外，单独的PKC激活就足以赋予对ALK抑制剂的抗性，而联合抑制ALK和PKC可恢复敏感性。与未经治疗的对照相比，我们在克唑替尼耐药的ALK重排肺肿瘤中观察到与几种抗性驱动因素（包括P2Y受体）相关的基因特征富集，支持这些已确定机制在临床ALK抑制剂抗性中发挥作用。
