HEXIM1 as a robust pharmacodynamic marker for monitoring target engagement of BET family bromodomain inhibitors in tumors and surrogate tissues
2017
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET
bromodomaininhibitor OTX015 using literature-described putative pharmacodynamic (PD) markers such as c-Myc, BRD2, etc. failed to detect PD marker responses in AML patients treated at active dose and those with clinical responses. Here we report the identification and characterization of HEXIM1 and other genes as robust PD markers for
BET inhibitors. Global gene expression profiling studies were carried out using cancer cells and surrogate tissues such as whole blood and skin to identify genes that are modulated by BET family proteins. Candidate markers were further characterized for concentration- and time-dependent responses to the
BET inhibitorABBV-075 in vitro and in vivo. HEXIM1 was found to be the only gene that exhibited robust and consistent modulation by
BET inhibitorsacross multiple cancer indications and surrogate tissues. Markers such as SERPINI1, ZCCHC24, and ZMYND8 were modulated by ABBV-075 and other
BET inhibitorsacross cancer cell lines and xenograft tumors but not in blood and skin. Significant down-regulation of c-Myc, a well-publicized target of
BET inhibitors, was largely restricted to
hematological cancercell lines. Incorporating well-characterized PD markers such as HEXIM1 and other genes described here can provide a better understanding of potential efficacy and toxicity associated with inhibiting BET family proteins and informs early clinical decisions on
BET inhibitordevelopment programs.
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