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

Abstract

Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops1,2,3,4. 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 resistance5. 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 ALK5,6—and further therapeutic options are limited5. 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.

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Figure 1: Complementary shRNA screens and high-throughput drug combination screens identify therapeutic approaches to overcome resistance in ALK-rearranged PDCs.
Figure 2: The SHP2 inhibitor SHP099 attenuates ceritinib-induced ERK reactivation and increases ceritinib efficacy in vitro.
Figure 3: Combined inhibition of ALK and SHP2 enhances response and overcomes resistance in drug-resistant ALK-rearranged PDCs in vivo.

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Acknowledgements

We thank D. Rakiec for help with NGS and C. Liu for help with in vivo experiments. This study was supported by grants from Novartis Institutes for BioMedical Research, American Association for Cancer Research (AACR)–AstraZeneca Fellowship in Lung Cancer Research (17-40-12-DARD to L.D.), National Cancer Institute (R01CA164273 to A.T.S.), the Wellcome Trust (102696 to C.H.B.) and the National Foundation for Cancer Research (to A.T.S.), by Be a Piece of the Solution and by LungStrong.

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L.D., F.L., A.T.S., A.N.H., C.H.B. and J.A.E. designed the study and analyzed the data. L.D., C.H.B. and J.A.E. wrote the paper. G.C., F.L., J.A.E. and C.H.B. supervised the studies. L.D., F.L., M.S., P.F., S.Y., K.Y., Y. Cao, Y. Chen, K.X.S. and E.L. performed cell line and biochemical studies. L.D., D.T.M., J.L. and H.Q.W. performed tumor xenograft studies. M.P., R.H.D. and D.L. developed or maintained patient-derived cell lines. G.K., F.L. and D.R. performed shRNA screen analyses. M.S.L. and A.L. performed NGS analysis. J.F.G., I.D.-J., L.F., E.L., S.M., H.H., M.M., M.L., J.W., K.H. and G.C. were involved with the study design. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Cyril H Benes or Fang Li or Jeffrey A Engelman.

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Competing interests

H.Q.W., P.F., G.K., K.Y., J.L., Y. Cao, Y. Chen, E.L., D.R., S.M., H.H., M.M., M.L., J.W., K.H., G.C., F.L. and J.A.E. are employees of Novartis. J.F.G. has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad, Loxo, Incyte, Novartis, Merck and Clovis. A.T.S. has served as a compensated consultant or received honoraria from Pfizer, Novartis, Genentech, Roche, Ignyta, Blueprint Medicine, Daiichi-Sankyo, Ariad, Chugai, Taiho Pharmaceuticals and EMD Serono. C.H.B. has received research funding from Novartis and Amgen. A.N.H. has received research funding from Novartis, Relay Therapeutics and Amgen. The remaining authors have no financial interests to declare.

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Dardaei, L., Wang, H., Singh, M. et al. SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med 24, 512–517 (2018). https://doi.org/10.1038/nm.4497

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