MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies

Cell Death Dis. 2015 Jan 15;6(1):e1593. doi: 10.1038/cddis.2014.525.

Abstract

Overexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we investigated the mechanisms of resistance that develops to ABT-199 therapy by generating ABT-199-resistant (ABT199-R) cell lines via chronic exposure of NHL cell lines to ABT-199. Acquired resistance resulted in substantial AKT activation and upregulation of MCL-1 and BCL-xL levels that sequestered BIM. ABT199-R cells exhibited increased MCL-1 stability and failed to activate BAX in response to ABT-199. The ABT-199 acquired and inherent resistant cells were sensitized to treatment with ABT-199 by inhibitors of the PI3K, AKT, and mTOR pathways, NVP-BEZ235 and GS-1101. NVP-BEZ235, a dual inhibitor of p-AKT and mTOR, reduced MCL-1 levels causing BIM release from MCL-1 and BCL-xL, thus leading to cell death by BAX activation. The PI3Kδ inhibitor GS-1101 (idelalisib) downregulated MCL-1 and sensitized ABT199-R cells through AKT-mediated BAX activation. A genetic approach, through siRNA-mediated down-regulation of AKT, MCL-1, and BCL-xL, significantly decreased cell survival, demonstrating the importance of these cell survival factors for ABT-199 resistance. Our findings suggest a novel mechanism that modulates the expression and activity of pro-survival proteins to confer treatment resistance that could be exploited by a rational combination therapeutic regimen that could be effective for treating lymphoid malignancies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / pharmacology
  • Lymphoma / enzymology*
  • Lymphoma / genetics
  • Lymphoma / pathology
  • Membrane Proteins / metabolism
  • Models, Biological
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein Stability / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Purines / pharmacology
  • Quinazolinones / pharmacology
  • Quinolines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sulfonamides / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*
  • Up-Regulation / drug effects
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imidazoles
  • MCL1 protein, human
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins
  • Purines
  • Quinazolinones
  • Quinolines
  • RNA, Messenger
  • Sulfonamides
  • bcl-X Protein
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • venetoclax
  • dactolisib
  • idelalisib