Supplementary Materials

Supplementary Material for:

Statins enhance efficacy of venetoclax in blood cancers

J. Scott Lee, Andrew Roberts*, Dennis Juarez, Thanh-Trang T. Vo, Shruti Bhatt, Lee-or Herzog, Sharmila Mallya, Richard J. Bellin, Suresh K. Agarwal, Ahmed Hamed Salem, Tu Xu, Jia Jia, Lingxiao Li, John R. Hanna, Matthew S. Davids, Angela G. Fleischman, Susan O'Brien, Lloyd T. Lam, Joel D. Leverson, Anthony Letai, Jonathan H. Schatz, David A. Fruman*

*Corresponding author. Email: dfruman{at}uci.edu (D.A.F.); awroberts{at}comcast.net (A.R.)

Published 13 June 2018, Sci. Transl. Med. 10, eaaq1240 (2018)
DOI: 10.1126/scitranslmed.aaq1240

This PDF file includes:

  • Materials and Methods
  • Fig. S1. Simvastatin enhances the effects of venetoclax on a subset of AML and DLBCL cell lines.
  • Fig. S2. Statins synergize with venetoclax in blood cancer cells.
  • Fig. S3. Simvastatin plus venetoclax induce apoptosis in DLBCL and AML cell lines.
  • Fig. S4. Simvastatin enhances killing of primary CLL samples cultured with stimuli from the microenvironment.
  • Fig. S5. Statins induce dose-dependent increase in mitochondrial priming but do not sensitize to chemotherapy.
  • Fig. S6. The combination of statin with venetoclax extends survival of mice with syngeneic B cell lymphoma.
  • Fig. S7. The effect of statins is due to on-target HMGCR inhibition.
  • Fig. S8. Mevalonate and GGPP are sufficient to rescue from the effects of simvastatin.
  • Fig. S9. Simvastatin inhibits protein geranylgeranylation in a dose-dependent manner in DLBCL.
  • Fig. S10. Inhibition of GGT is sufficient to recapitulate the effects of simvastatin in AML cell lines.
  • Fig. S11. Simvastatin does not affect expression of many major BCL2 family proteins but does increase PUMA.
  • Fig. S12. Simvastatin increases association of BCL2 with PUMA in sensitive OCI-AML3 cells but not in resistant OCI-LY1 cells.
  • Fig. S13. PUMA knockdown in OCI-AML3 cells rescues them from sensitization to venetoclax by simvastatin.
  • Fig. S14. Statins increase PUMA expression through a mechanism independent of p53 in DLBCL and AML cells.
  • Fig. S15. Statin use is associated with longer PFS in CLL patients treated in venetoclax clinical trials.
  • Fig. S16. Response to venetoclax was enhanced in CLL clinical trials among patients who received the 400-mg statin dose.
  • Fig. S17. Statins do not affect venetoclax pharmacokinetics.
  • Table S1. Characteristics of CLL patient samples.
  • Table S2. Characteristics of CLL patients in three clinical trials of venetoclax monotherapy grouped by background statin use.
  • Table S3. Adverse events in CLL patients in three clinical trials of venetoclax monotherapy grouped by background statin use.

[Download PDF]

Other Supplementary Material for this manuscript includes the following:

  • Table S4 Raw data (in a separate Excel file).