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Supplementary Tables and Figures from Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance

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posted on 2023-04-03, 16:42 authored by Ida Aronchik, Yumin Dai, Matt Labenski, Carmen Barnes, Terri Jones, Lixin Qiao, Lisa Beebe, Mehnaz Malek, Winfried Elis, Tao Shi, Konstantinos Mavrommatis, Gordon L. Bray, Ellen H. Filvaroff

Table S1. Summary of CC-90003 specificity data resulting from cellular and biochemical assays. Table S2. Response of BRAF mutant cell lines to CC-90003 ERK 1/2 inhibition. Table S3. Summary of dose finding efficacy study in HCT-116 xenograft model. Figure S1. CC-90003 Mass spectrometry analysis of CC-90003 covalent ERK1/2 binding. Figure S2. CC-90003 Inhibits proliferation and induces apoptosis in a panel of KRAS mutant Lung, Pancreatic and Colorectal cancer cell lines. Figure S3. Assessment of ERK inhibitor PD markers in BRAF and KRAS mutant Cancer Models. Figure S4. CC-90003 inhibits proliferation of a subset of BRAF and KRAS mutant cell lung cancer lines and induces cell death more robustly, compared to published inhibitors. Figure S5. CC-90003 inhibits colony formation in a set of KRAS mutant PDX models ex vivo. Figure S6. CC-90003 does not reduce body weights of animals bearing KRAS mutant PDX derived tumors. Figure S7. Genes differentially expressed in CXF-243 PDX model compared to other models used in the study. Figure S8. Genes differentially expressed in CXF-243, CXF-975 and CXF-1034 PDX models compared to other models used in the study. Figure S9. Combination of CC-90003 with EGFR inhibitor Afatinib and NK inhibitor JNK-IN-8. Figure S10. Quantification of Western Blot data in Figure 4. Figure S11. CC-90003 does not reduce body weights of animals bearing LXFA-1674 KRAS mutant lung cancer PDX derived tumors. Figure S12. Regrowth of LXFA-1674 KRAS mutant lung cancer PDX derived tumors following discontinuation of treatment by Docetaxel and CC-90003 combination with Docetaxel. Figure S13. CC-90003 alone and in combination with Docetaxel modulates stemness program in ex vivo serial passaging Mammocult assay.

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ARTICLE ABSTRACT

As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming. Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.

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