Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma
Emily Rychak, Derek Mendy, Tao Shi, Yuhong Ning, Jim Leisten, Ling Lu, Karen Miller, Rama K Narla, Robert Z Orlowski, Heather K Raymon, Chad C Bjorklund, Anjan Thakurta, Anita K Gandhi, Brian E Cathers, Rajesh Chopra, Thomas O Daniel, Antonia Lopez-Girona, Emily Rychak, Derek Mendy, Tao Shi, Yuhong Ning, Jim Leisten, Ling Lu, Karen Miller, Rama K Narla, Robert Z Orlowski, Heather K Raymon, Chad C Bjorklund, Anjan Thakurta, Anita K Gandhi, Brian E Cathers, Rajesh Chopra, Thomas O Daniel, Antonia Lopez-Girona
Abstract
Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide-sensitive H929 MM cell lines, were also observed in PomDex-treated lenalidomide-resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide-sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex-treated samples, highlighted by the modulation of pro-apoptotic pathways in lenalidomide-resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide-resistant setting.
Keywords: anti-proliferative; apoptosis; dexamethasone; myeloma; pomalidomide; resistance.
© 2016 John Wiley & Sons Ltd.
Source: PubMed