Danusertib and bosutinib work together to overcome resistance to imatinib for chronic myeloid leukemia (CML) with mutated BCR-ABL gatekeeper genes. The BCR-ABL mutation confers resistance to all currently approved kinase inhibitors for chronic myeloid leukemia.
Uwe Rix, PhD, of Moffitt Cancer Center and study co-author, explained that, “Treatment of chronic myeloid leukemia rapidly improved after the introduction of the first BCR-ABL inhibitor, imatinib (Gleevec). However, it soon became apparent that a broad spectrum of possible resistance mechanisms necessitated second- and third-generation BCR-ABL inhibitors. Although these are mostly very successful, none of the currently approved options has been effective in patients with chronic myeloid leukemia who harbor the BCR-ABL gatekeeper mutation.”
The research team investigated the molecular mechanisms and logic that underlie the synergistic interaction between danusertib and bosutinib, which are specific for BCR-ABL gatekeeper mutation-transformed cells. Their novel systems pharmacology approach combined different proteomics and gene expression profiling methods.
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Their research approach found previously unappreciated features of both agents. Rix explained that the predominantly affected pathway was the downstream MAPK signaling cascade. Both compounds inhibited c-MYC, which is a gene regulator that codes a transcription factor with a well-established but not well understood role in a broad spectrum of human cancers.
“In the context of chronic myeloid leukemia, c-MYC is required for BCR-ABL-mediated transformation,” Rix explained. “What is intriguing is that chronic myeloid leukemia cells with the BCR-ABL gatekeeper mutation seem to be more dependent on the MAPK/c-MYC signaling axis than BCR-ABL wild-type cells. Thus, challenging c-MYC with drugs appears promising in these resistant cells, but steps have only recently been made.”
The research team concluded that they unraveled the synergistic interaction between danusertib and bosutinib in a clinically relevant, highly drug-resistant disease setting. Their work revealed a nonobvious synergistic mechanism by several off-targets of the two small molecules.
This research was published in Nature Chemical Biology (2012; doi:10.1038/nchembio.1085).
