Supplementary Materials

The PDF file includes:

  • Materials and Methods
  • Fig. S1. Biological characterization of residual disease after prolonged treatment with cetuximab in representative mCRC PDXs.
  • Fig. S2. Analysis of adaptive changes versus clonal selection induced by cetuximab in representative mCRC PDXs.
  • Fig. S3. ChIP-seq analysis of residual disease after prolonged treatment with cetuximab in representative mCRC PDXs.
  • Fig. S4. Longitudinal analysis of β-catenin abundance at different time points during prolonged treatment with cetuximab in representative mCRC PDXs.
  • Fig. S5. GSEA of residual PDXs with signatures of Paneth cells and deep secretory cells.
  • Fig. S6. DEFA5 and β-catenin double staining in representative mCRC PDXs treated with cetuximab.
  • Fig. S7. Transcript and protein changes of Paneth-cell markers and global gene expression variations in representative mCRC PDXs during cetuximab treatment and after therapy suspension.
  • Fig. S8. Abundance of YAP and expression of YAP targets in representative mCRC PDXs during different time points of cetuximab treatment and after therapy suspension.
  • Fig. S9. Inhibition of YAP activity and expression of YAP-dependent genes by cetuximab in CRC cell lines.
  • Fig. S10. Expression of secretory/Paneth cell genes after YAP silencing in CRC cell lines.
  • Fig. S11. YAP-dependent regulation of Wnt target genes in CRC cell lines.
  • Fig. S12. Modulation of YAP transcriptional activity by cetuximab and other inhibitors of the EGFR pathway in CRC cell lines.
  • Fig. S13. Abundance and activity of doxycycline-inducible YAP-5SA and modulation of secretory/Paneth cell genes by EGFR pathway inhibition in vitro and in vivo.
  • Fig. S14. Expression of secretory/Paneth cell genes after YAP silencing or YAP overexpression in vitro and in vivo.
  • Fig. S15. Modulation of EGFR family ligands in mCRC PDXs treated with cetuximab.
  • Fig. S16. Effects of individual signal inhibition and dual blockade of EGFR and PI3K or EGFR and MEK in CRC cell cultures.
  • Fig. S17. Effects of cetuximab on downstream signals in vitro.
  • Fig. S18. Effects of cetuximab on downstream signals in vivo.
  • Fig. S19. Effects of PI3K inhibitors on downstream signals and tumor growth in vivo.
  • Fig. S20. Effects of PI3K inhibition and combined EGFR and PI3K inhibition on mCRC PDX macroscopic residual disease.
  • Fig. S21. Effects of combined EGFR and PI3K inhibition on mCRC PDX microscopic residual disease, apoptosis, and survival.
  • Fig. S22. YAP-dependent transcriptional modulation of HER2 and HER3 in CRC cell lines.
  • Fig. S23. Modulation of HER2 and HER3 expression in mCRC PDXs during prolonged treatment with cetuximab.
  • Fig. S24. DEFA5 and HER2/HER3 double staining in representative mCRC PDXs treated with cetuximab.
  • Fig. S25. CRC cell line sensitivity to individual targeting of HER family members.
  • Fig. S26. Effects of cetuximab or Pan-HER on EGFR downstream targets in vivo.
  • References (62–64)

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Other Supplementary Material for this manuscript includes the following:

  • Data file S1 (Microsoft Excel format). List of genes subject to mutational and gene copy number analysis.
  • Data file S2 (Microsoft Excel format). GSEA of gene expression changes induced by cetuximab in mCRC PDXs.
  • Data file S3 (Microsoft Excel format). Ingenuity Pathway Analysis of gene expression changes induced by cetuximab in mCRC PDXs.
  • Data file S4 (Microsoft Excel format). Expression changes of secretory/Paneth cell genes induced by cetuximab in the reference collection (GSE108277).
  • Data file S5 (Microsoft Excel format). Basic clinical characteristics of patients treated with Sym004.
  • Data file S6 (Microsoft Excel format). Original data.
  • Data file S7 (Microsoft Excel format). Taqman probes used for RT-qPCR.

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