Supplementary Figures 1 - 6 from Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling

Schoumacher, Marie; Hurov, Kristen E.; Lehár, Joseph; Yan-Neale, Yan; Mishina, Yuji; Sonkin, Dmitriy; Korn, Joshua M.; Flemming, Daisy; Jones, Michael D.; Antonakos, Brandon; Cooke, Vesselina G.; Steiger, Janine; Ledell, Jebediah; Stump, Mark D.; Sellers, William R.; Danial, Nika N.; Shao, Wenlin

doi:10.1158/0008-5472.22403517.v1

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Supplementary Figures 1 - 6 from Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling

journal contribution

posted on 2023-03-30, 22:45 authored by Marie Schoumacher, Kristen E. Hurov, Joseph Lehár, Yan Yan-Neale, Yuji Mishina, Dmitriy Sonkin, Joshua M. Korn, Daisy Flemming, Michael D. Jones, Brandon Antonakos, Vesselina G. Cooke, Janine Steiger, Jebediah Ledell, Mark D. Stump, William R. Sellers, Nika N. Danial, Wenlin Shao

PDF file - 660KB, Supplementary Figure S1. All RAS mutant cell lines have a higher sensitivity to the TNKSi/MEKi combination. Supplementary Figure S2. Validation of TNKSi/MEKi combination in KRAS mutant cancer cells. Supplementary Figure S3. Combinations with MEK inhibitor in the SW480 cell line. Supplementary Figure S4. TNKSi/MEKi combination leads to enhanced inhibition of AKT signaling activity. Supplementary Figure S5. TNKSi potentiates MEKi by releasing a feedback loop on FGFR2 signaling. Supplementary Figure S6. Consequences of combined inhibition of TNKS and MEK on FGFR2 and AKT signaling pathways in KRAS mutant cell lines.

History

ARTICLE ABSTRACT

Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism. Cancer Res; 74(12); 3294–305. ©2014 AACR.