SHP2 Inhibition Overcomes Adaptive and Acquired Resistance to FLT3 TKI to Improve Efficacy Against FLT3/ITD AML

作者：Tessa Seale, Li Li, J. Kyle Bruner, Bao Nguyen, Mark J. Levis, Christine A. Pratilas, Donald Small · 发表于：Blood · 年份：2023 · DOI：10.1182/blood-2023-184338 · 被引用次数：2 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Protein Tyrosine Phosphatases、Synthesis and biological activity

FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase (RTK) that is frequently mutated in acute myeloid leukemia (AML), with the internal tandem mutation (FLT3/ITD) conferring a poor prognosis to AML patients. This makes FLT3/ITD AML a validated target for treatment with tyrosine kinase inhibitors (TKI), but their success has been hindered by mechanisms of resistance including rapid signal reprogramming known as adaptive resistance and acquired resistance gained through long-term treatment. Past work from our lab has shown that FLT3/ITD cells undergo adaptive resistance, through the rapid reactivation of ERK signaling within 24 hours of sustained FLT3 inhibition. To improve therapy of FLT3/ITD AML it is important to identify therapeutic targets that overcome this ERK reactivation. Since adaptive ERK reactivation is often due to the relief of negative feedback loops that result in the activation of other RTK, we performed an RTK phospho-array on the FLT3/ITD cell line MV4;11. 48-hour treatment with the FLT3 TKI sorafenib resulted in increased activation of IGF-R, HER3 and AXL. While recent work from our lab found that combining AXL and FLT3 inhibition abrogated the ERK reactivation and exerted greater antileukemic effects, the activation of multiple RTKs suggests that targeting a signaling hub that inhibits multiple RTKs at once will likely prove more efficacious in overcoming this adaptive response. Recent literature has implicated SH2-containing protein tyrosine ph...