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Cancer Discov. 2018 Oct;8(10):1237-1249. doi: 10.1158/2159-8290.CD-18-0444. Epub 2018 Jul 25.

SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models.

Author information

1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York. Benjamin.Neel@nyumc.org KwanHo.Tang@nyumc.org Carmine.Fedele@nyumc.org.
2
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York.
3
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, New York.
4
Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, New York.

Abstract

Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies.Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237-49. ©2018 AACR. See related commentary by Torres-Ayuso and Brognard, p. 1210 This article is highlighted in the In This Issue feature, p. 1195.

PMID:
30045908
PMCID:
PMC6170706
[Available on 2019-10-01]
DOI:
10.1158/2159-8290.CD-18-0444

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