Researchers developed a novel multikinase FLT3-IRAK1/4 inhibitor (NCGC1481) that removed adaptively resistant FLT3-mutant AML cells, as detailed in a study published in Science Translational Medicine. This inhibitor is more effective than current targeted FLT3 treatments like gilteritinib.
“The identification of oncogenic kinases and small molecules designed to target active, functionally relevant kinases has revolutionized cancer treatment,” Katelyn Melgar, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati. “Frustratingly, although many of these targeted inhibitors initially demonstrate encouraging clinical responses, most patients relapse as a result of primary or acquired resistance.”
Relapse after therapy with oncogenic kinases is usually secondary to either target-dependent mechanisms, which diminish enzyme-inhibitor binding, or target-independent mechanisms, including adaptive resistance, which refers to the alternative activation of pathways involved in survival and proliferation.
In the current mechanistic study, Melgar et al. analyzed integrative in-cell kinase and gene regulatory network responses following oncogenic signaling blockade by FLT3 inhibitors in FLT3-mutant AML. They found that compensatory activation of innate immune stress response pathways results in adaptive resistance. Furthermore, IRAK1/4 inhibition using FLT3 inhibitors targets adaptively resistance mutant clones. IRAK1/4 activation in FLT3 inhibitor-treated AML re-established Ras/MAPK signaling, as well as NF-ƘB. Following tyrosine kinase inhibition, this mechanism constitutes a major form of resistance.
Cells initiate cellular stress responses for survival. These stress pathways have been elucidated, and recent research has demonstrated that proteins in cellular stress responses regulate signaling intermediates that activate immune-related pathways. In the current study, inflammatory stress response pathways were demonstrated to play a role in adaptive resistance in FLT3-mutant AML. Moreover according to the authors, this mechanism may be important in other types of cancer cells sustaining a stress responses post-therapy
“Although we report that FLT3i treatment resulted in TLR9 overexpression and IRAK1/4 activation, the precise mechanism of innate immune signaling and specifically IRAK1/4 activation after targeted therapy is not resolved and may involve various cellular stress response pathways,” wrote the authors.
Other studies are exploring the suppression of parallel-signaling pathways following use of targeted therapies, including extracellular signal-regulated kinase and MAPK kinase. Ras/MAPK signaling leads to adaptive resistance in FLT3-mutant AML but focusing on only a single arm of the signal cascade has resulted in limited clinical utility. Instead, Melgar et al. hypothesized that targeting IRAK1/4 will result in durable inhibition of bypass signaling cascades, prevention of adaptive resistance, and enhancement of clinical efficacy because the IRAK1/4 complex lies upstream of Ras/MAPK and NF-ƘB.
The team discovered that using NCGC1481 to target IRAK1 or IRAK4, as well as FLT3, is the best way to combat adaptive resistance that happens when targeting FLT3, and outperforms the use of gilteritinib, which exhibits limited inhibition of IRAK1/4 at higher concentrations, and is less effective at stopping adaptive resistance due to treatment in FLT3-mutant AML.
“Although further studies are needed, our study demonstrates that therapies that simultaneously inhibit FLT3 signaling and compensatory IRAK1/4 activation have the potential to improve the therapeutic efficacy in patients with FLT3-mutant AML,” concluded the authors.