Overcoming adaptive therapy resistance in AML by targeting immune response pathways

Abstract

Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course; however, most patients will relapse because of target-dependent mechanisms that mitigate enzyme-inhibitor binding or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here, we describe mechanisms of adaptive resistance in FMS-like receptor tyrosine kinase (FLT3)–mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the interleukin-1 receptor–associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multikinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-mutant AML cells in vitro and in vivo and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways.

Targeting AML-associated FLT3 mutations with a type I kinase inhibitor

“…In summary, we have identified a small-molecule inhibitor of clinically relevant FLT3 mutants that exploits a unique binding pose that is unaffected by common active site mutations in FLT3 and, consequently, retains remarkable cytotoxic potential versus FLT3-mutant AML cells harboring these mutations both in vitro and in vivo. We recently reported that NCGC1481 was also effective at overcoming adaptive resistance to FLT3 inhibitors in AML by targeting immune signaling pathways via direct inhibition of IL-1 receptor-associated kinase 1 (IRAK1) and IRAK4 (15). Collectively, these data support the possibility that NCGC1481 can…”

“…Profiling of a series of small-molecule kinase inhibitors highlighted a previously reported series of 3-(pyridin-2-yl)imidazo [1,2-a]pyridines as potent inhibitors of FLT3 (15). We pursued a detailed evaluation of the structure activity relationships that govern this chemotype's activity versus FLT3 and versus FLT3-mutant AML.…”

“…), and no observable hematologic toxicity in mice. NCGC1481 demonstrates 10-fold or greater selectivity versus more than 80% of tested kinases relative to FLT3 in biochemical assays using purified proteins and high kinase selectivity in situ (15). We next profiled NCGC1481 versus a commercial panel of known, clinically relevant mutations at the FLT3 TKD.…”

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

“…One study stated that IL-4 can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors such as ibrutinib in CLL cells (Blunt et al 2017 ). Another study reported that innate immune pathway activation via the interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells (Melgar et al 2019 ). This result supports our observation about the association of immune response pathways with drug resistance.…”

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

“…However BCOR mutations alone show sensitivity to the multi-kinase inhibitor crizotinib ( 9 ). Interestingly, targeting the IL-1 pathway with the multi-kinase inhibitor, pacritinib, which inhibits IRAK1/4, FLT3, and JAK2, highlights robust sensitivity despite adaptive resistance to therapies and significant AML cell death ( 174 , 175 ). Further investigations are ongoing ( 176 ).…”