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Table 1 Pre-clinical studies of EZH2 inhibitors in MM

From: EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies

Author (date)

EZH2 inhibitor

Model

Main findings

Ref.

Hernando et al. (2015)

E7438 (EPZ-6438)

MM cell lines

Cells become more adherent and less proliferative with EZH2 inhibition

[18]

Mouse model

Slower progression of the tumor, with no effect on body weight

Agarwal et al. (2016)

UNC1999a and GSK343

MM cell lines and patient samples

Reduced viability in a dose and time-dependent manner via induction of apoptosis

[23]

Zeng et al. (2017)

GSK126

MM cell lines

Decreased proliferation and increased apoptosis, reduction in stem-cell like MM cells with EZH2 inhibition

[19]

Mouse model

Slower progression of the tumor

Pawlyn et al. (2017)

EPZ005687 and UNC1999a

MM cell lines and patient samples

EZH2 inhibition reduces MM cell viability by inducing cell cycle arrest and apoptosis

[21]

Honma et al. (2017)

OR-S2a

MM cell lines

6 out of 8 cell lines are hypersensitive to dual EZH1/2 inhibition

[33]

Rizq et al. (2017)

UNC1999a

MM cell lines and patient samples

UNC1999 inhibited the growth of MM cell lines including resistant ones; cytotoxicity in MM patients cells, but not healthy donors; enhanced the cytotoxicity induced by bortezomib

[22]

Mouse model

Reduced tumor growth; UNC1999 enhanced the cytotoxicity induced by bortezomib

Alzrigat et al. (2017)

UNC1999a

MM cell lines and primary MM cells

Combining UNC1999 and BMI-1 inhibitor PTC-209 induces a significant reduction in cell viability compared to single agent

[34]

Dimopoulos et al. (2018)

EPZ-6438

MM cell lines resistant to IMiD

Combination of 5-Aza and EPZ-6438 could re-sensitize 7 of 8 cell lines to IMiD

[26]

Rastgoo et al. (2018)

EPZ-6438

MM cell lines and primary MM cells

EPZ-6438 reversed bortezomib resistance, combination with bortezomib revealed more pronounced effect on drug resistant cell lines

[17]

Mouse model

Combination of bortezomib and EPZ-6438 significantly reduced the tumor size and prolonged the survival

Combinations

 Neo et al. (2014)

GSK126

MM cell line (MM1S)

The dose of GSK126 required for growth inhibition and death was reduced by the addition of PTX

[36]

 Harding et al. (2018)

GSK126, EPZ-6438, UNC1999

MM cell lines

Pre-treatment with EZH2 inhibitors sensitized cells to panobinostat regardless of sensitivity to single agent EZH2 inhibitor

[37]

 Herviou et al. (2018)

EPZ-6438

MM cell lines and primary MM cells

EPZ-6438 reduced the number of viable cells in 9/17 patients, without correlation with EZH2 expression.

[20]

EPZ-6438 sensitized cells to lenalidomide and pre-treatment with EPZ-6438 could overcome lenalidomide resistance in resistant cell lines

  1. aNote: OR-S2 and UNC1999 are dual EZH1/2 inhibitors