TY - JOUR
T1 - Epigenetic modulation reveals differentiation state specificity of oncogene addiction
AU - Khaliq, Mehwish
AU - Manikkam, Mohan
AU - Martinez, Elisabeth D.
AU - Fallahi-Sichani, Mohammad
N1 - Funding Information:
We thank Meenhard Herlyn for advice. We also thank Noah Brown, LaJuanda Carter, and members of the Fallahi-Sichani laboratory for help and discussion. This work was supported by the University of Michigan, University of Virginia, and awards from the Elsa Pardee Foundation and V Foundation for Cancer Research V2017-011, Department of Defense PRCRP Career Development Award W81XWH1810427, NIH grants R00-CA194163 and R35-GM133404 (to M.F.S.), P30-CA046592 (University of Michigan Rogel Cancer Center), P30-CA044579 (University of Virginia Cancer Center), NCI Training Grant award T32-CA009676 (to M.K.), the Welch Foundation I-1878 and CPRIT RP160493 (to E.D.M.) and NCI SPORE grant P50-CA070907.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells’ differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.
AB - Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells’ differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.
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U2 - 10.1038/s41467-021-21784-2
DO - 10.1038/s41467-021-21784-2
M3 - Article
C2 - 33750776
AN - SCOPUS:85102239447
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1536
ER -