Supplementary Materials

Supplementary Material for:

Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS

Sarah J. Ross, Alexey S. Revenko, Lyndsey L. Hanson, Rebecca Ellston, Anna Staniszewska, Nicky Whalley, Sanjay K. Pandey, Mitchell Revill, Claire Rooney, Linda K. Buckett, Stephanie K. Klein, Kevin Hudson, Brett P. Monia, Michael Zinda, David C. Blakey, Paul D. Lyne,* A. Robert Macleod*

*Corresponding author. Email: paul.lyne{at}astrazeneca.com (P.D.L.); rmacleod{at}ionisph.com (A.R.M.)

Published 14 June 2017, Sci. Transl. Med. 9, eaal5253 (2017)
DOI: 10.1126/scitranslmed.aal5253

This PDF file includes:

  • Materials and Methods
  • Fig. S1. Effect of AZD4785 on KRAS, DUSP6, and ETV4 mRNA expression in KRAS mutant and KRAS wild-type cell lines.
  • Fig. S2. Sensitivity of NSCLC lines to KRAS knockdown by ASO in 2D versus 3D growth assays.
  • Fig. S3. Effect of AZD4785 on colony formation in KRAS mutant and KRAS wild-type cell lines.
  • Fig. S4. Effect of AZD4785, selumetinib, and SCH772984 on the proliferation of KRAS mutant and KRAS wild-type cell lines.
  • Fig. S5. Effect of AZD4785, selumetinib, and SCH772984 on signaling in KRAS mutant and KRAS wild-type cell lines.
  • Fig. S6. Effects of AZD4785 and selumetinib combination on signaling and proliferation of NSCLC cells.
  • Fig. S7. In vivo study assessing the kinetics of tumor PD and liver PK of AZD4785.
  • Fig. S8. Effect of AZD4785 treatment on HRAS and NRAS expression in the NCI-H358 xenograft model.
  • Fig. S9. Tolerability of AZD4785 treatment in xenograft studies.
  • Fig. S10. Waterfall plots of xenograft and PDX studies.
  • Fig. S11. PD and efficacy of AZD4785 and additional cEt KRAS ASOs in the NCI-H358 model.
  • Fig. S12. Selectivity of murine KRAS ASOs and impact on MAPK pathway signaling in liver tissue from mice.
  • Fig. S13. Summary of the effects of the murine KRAS ASOs on body weight, plasma chemistry, and circulating blood cells in mice.
  • Fig. S14. Selectivity of AZD4785 and impact on MAPK pathway signaling in liver tissue from monkeys.
  • Fig. S15. Impact of murine KRAS ASOs on plasma concentrations of inorganic phosphates and calcium.
  • Table S1. Summary of predicted off-targets for AZD4785.
  • Table S2. Details of the cell lines used in the study.
  • Table S3. Activity of AZD4785 in KRAS mutant NSCLC xenograft models.
  • Table S4. Inhibition of KRAS mRNA across a panel of normal tissues after treatment of mice with murine KRAS ASOs.
  • Table S5. Summary of tissue histopathology in the mouse tolerability study after treatment with the murine-selective KRAS ASOs.
  • Table S6. Summary of body and organ weights, plasma chemistries, and circulating blood cells in the mice after treatment with the murine-selective KRAS ASOs.
  • Table S7. Summary of tissue histopathology in the monkey tolerability study after treatment with AZD4785.
  • Table S8. Summary of body and organ weights in the monkey tolerability study after AZD4785 treatment.
  • Table S9. Summary of circulating blood cells in the monkey tolerability study after AZD4785 treatment.
  • Table S10. Summary of plasma chemistries in the monkey tolerability study after AZD4785 treatment.
  • Table S11. Summary of urinalysis in the monkey tolerability study after AZD4785 treatment.
  • Table S12. Details of the parameters used for analyzing colony formation across the cell line panel.
  • Table S13. Summary of the individual animal tumor volumes in the xenograft and PDX studies.
  • References (52, 53)

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