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Figure S1-S7 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

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posted on 2023-04-03, 21:22 authored by Carmine Fedele, Hao Ran, Brian Diskin, Wei Wei, Jayu Jen, Mitchell J. Geer, Kiyomi Araki, Ugur Ozerdem, Diane M. Simeone, George Miller, Benjamin G. Neel, Kwan Ho Tang
<p>Supplementary Figure S1: Combined SHP2/MEK inhibition prevents adaptive resistance in PDAC and NSCLC lines Supplementary Figure S2: SHP2 inhibition abrogates MEK-I-evoked reactivation of the ERK MAPK pathway Supplementary Figure S3: Distinct mechanisms of resistance to MEK-I/SHP099 combination in PDAC lines Supplementary Figure S4: Development of tolerable SHP099/trametinib regimen Supplementary Figure S5: Combination decreases tumor cell proliferation and promotes programmed cell death (PDAC and NSCLC) Supplementary Figure S6: Combination decreases tumor cell proliferation and promotes programmed cell death (PDAC, TNBC and HGSC) Supplementary Figure S7: RTKs/RTK ligand expression and Annexin V/cell cycle analysis of TNBC and HGSC lines</p>

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ARTICLE 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