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Developing SHP2-based combination therapy for KRAS-amplified cancer
Tianxia Li, … , Daniel V.T. Catenacci, Adam J. Bass
Tianxia Li, … , Daniel V.T. Catenacci, Adam J. Bass
Published February 8, 2023
Citation Information: JCI Insight. 2023;8(3):e152714. https://doi.org/10.1172/jci.insight.152714.
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Research Article Oncology

Developing SHP2-based combination therapy for KRAS-amplified cancer

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Abstract

Gastroesophageal adenocarcinomas (GEAs) harbor recurrent amplification of KRAS, leading to marked overexpression of WT KRAS protein. We previously demonstrated that SHP2 phosphatase, which acts to promote KRAS and downstream MAPK pathway activation, is a target in these tumors when combined with MEK inhibition. We hypothesized that SHP2 inhibitors may serve as a foundation for developing novel combination inhibitor strategies for therapy of KRAS-amplified GEA, including with targets outside the MAPK pathway. Here, we explore potential targets to effectively augment the efficacy of SHP2 inhibition, starting with genome-wide CRISPR screens in KRAS-amplified GEA cell lines with and without SHP2 inhibition. We identify candidate targets within the MAPK pathway and among upstream RTKs that may enhance SHP2 efficacy in KRAS-amplified GEA. Additional in vitro and in vivo experiments demonstrated the potent cytotoxicity of pan-ERBB kinase inhibitions in vitro and in vivo. Furthermore, beyond targets within the MAPK pathway, we demonstrate that inhibition of CDK4/6 combines potently with SHP2 inhibition in KRAS-amplified GEA, with greater efficacy of this combination in KRAS-amplified, compared with KRAS-mutant, tumors. These results suggest therapeutic combinations for clinical study in KRAS-amplified GEAs.

Authors

Tianxia Li, Osamu Kikuchi, Jin Zhou, Yichen Wang, Babita Pokharel, Klavdija Bastl, Prafulla Gokhale, Aine Knott, Yanxi Zhang, John G. Doench, Zandra V. Ho, Daniel V.T. Catenacci, Adam J. Bass

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Figure 1

Genome-wide screen identified candidate targets that enhance sensitivity to an SHP2i.

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Genome-wide screen identified candidate targets that enhance sensitivity...
(A) Experimental scheme of genome-wide CRISPR anchor screening. KE-39 and HUG1-N KRAS-amp GEA cells were transduced with a genome-wide Brunello CRISPR-KO library and exposed to either 5 μM SHP099 or vehicle control to identify mediators of SHP099 sensitivity. Surviving cells from each virus infection were isolated, and the sgRNA sequences were amplified by PCR and sequenced. (B and C) Volcano plots of (B) HUG1-N and (C) KE-39 showing genes conferring resistance and sensitivity to SHP099. The LFC and –log10 (FDR) were calculated using the mean of the 4 sgRNAs per gene. P values were calculated using hypergeometric distribution. Red dots show RAS-related genes (RAS pathway 2.0). (D) Comparison of HUG1-N and KE-39 LFC data with a subset of RAS-related genes (RAS pathway 2.0 in red) and all other genes (blue). The list of top genes is provided in Supplemental Table 1.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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