Details

Autor(en) / Beteiligte

• Dardaei, Leila
• Wang, Hui Qin
• Singh, Manrose
• Fordjour, Paul
• Shaw, Katherine X
• Yoda, Satoshi
• Kerr, Grainne
• Yu, Kristine
• Liang, Jinsheng
• Cao, Yichen
• Chen, Yan
• Lawrence, Michael S
• Langenbucher, Adam
• Gainor, Justin F
• Friboulet, Luc
• Dagogo-Jack, Ibiayi
• Myers, David T
• Labrot, Emma
• Ruddy, David
• Parks, Melissa
• Lee, Dana
• DiCecca, Richard H
• Moody, Susan
• Hao, Huaixiang
• Mohseni, Morvarid
• LaMarche, Matthew
• Williams, Juliet
• Hoffmaster, Keith
• Caponigro, Giordano
• Shaw, Alice T
• Hata, Aaron N
• Benes, Cyril H
• Li, Fang
• Engelman, Jeffrey A

Titel

SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

Ist Teil von

• Nature Medicine, 2018-04, Vol.24 (4), p.512-517

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2018

Quelle

Elektronische Zeitschriftenbibliothek - Freely accessible e-journals

Beschreibungen/Notizen

• Genomic and drug screens identify SHP2 blockade as a therapeutic approach for ALK-rearranged non-small cell lung cancers developing resistance through ALK-mutant-independent mechanisms. Most anaplastic lymphoma kinase ( ALK )-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops 1 , 2 , 3 , 4 . Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK , while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance 5 . Such tumors are not expected to respond to lorlatinib—a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK 5 , 6 —and further therapeutic options are limited 5 . Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance.