Investigators evaluated whether AZD3463 can induce apoptosis in a dose-dependent manner in a subset of AML patients.
The ALK inhibitor AZD3463 appears to induce apoptosis in a dose-dependent manner and may have a role in helping patients with sorafenib-resistant acute myeloid leukemia (AML), according to a new study published in Blood Cancer Journal.
Sausan A. Moharram, of Lund University in Sweden, and colleagues examined the kinase-dependency of sorafenib-sensitive cells and sorafenib-resistant cells by employing a library of 378 kinase inhibitors. They found that AZD3463 inhibited sorafenib-sensitive and sorafenib-resistant cells equally well.
“The interesting finding was that an ALK inhibitor (AZD3463) was effective in killing cells with FLT3-ITD mutations, including those who had developed secondary mechanisms of resistance to a first-generation FLT3 inhibitor (sorafenib),” Jeffrey Lancet, MD, chair of the Moffitt Cancer Center's Department of Malignant Hematology, told Cancer Network. Although this was a non-clinical study utilizing cell lines and mice, the results are intriguing, he said.
Lancet also noted that the study is very important because it utilizes high-throughput screening of drugs that may have off-target effects, and this can potentially be repurposed for other cancer types beyond those for which it was originally designed.
Researchers conducted cell line studies and characterized sorafenib-sensitive and sorafenib-resistant cells with respect to tyrosine kinase signaling using peptide-based kinase profiling. They found that peptide substrates selective for PDGFRB, CSK, and FES displayed elevated tyrosine phosphorylation in sorafenib-resistant cells compared with sorafenib-sensitive cells.
AZD3463 has been shown to be potent in ALK-driven preclinical models and produced positive results in preclinical testing of neuroblastomas with ALK mutations. This agent also has been shown to be potent in a variety of crizotinib-resistant models. The current study demonstrated that AZD3463 inhibited FLT3-ITD selectively without affecting wild-type FLT3 signaling.
Lancet said it has been postulated that AZD3463 stereochemically fits into the ATP binding pocket of mutated FLT3, similar to quizartinib. If AZD3463 is further developed clinically for ALK-mutated tumors, there may be opportunity for it in the setting of FLT3-mutated AML as well. However, he noted that many second-generation FLT3 inhibitors have already been developed or are in development. “So, the setting in which a drug like AZD3463 would fit in is unclear,” Lancet told Cancer Network.
According to the authors, approximately 30% of patients with AML carry an internal tandem duplication (ITD) mutation in the type III receptor tyrosine kinase FLT3, and this patient population tends to have a poorer prognosis than other AML patient groups. Several inhibitors targeting FLT3 have undergone clinical trial testing and demonstrated a transient response with monotherapy. It is theorized that a combination approach is warranted, and these new findings may help better inform future clinical trials.