midostaurin

Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

First-generation inhibitors, such as midostaurin, provided the foundation for targeted therapy, while recently developed agents such as gilteritinib and quizartinib have shown more selectivity and demonstrated superior clinical efficiency and improved tolerability. This review discusses the significance of FLT-3 mutations, the evolution of targeted therapies, current treatment guidelines, and ongoing challenges such as resistance and high relapse rates. We also discuss the emerging combinations of therapies and novel agents currently in clinical trials that aim to overcome resistance and improve long-term outcomes for patients with FLT-3-mutated AML.

P3, N=214, Completed, Arog Pharmaceuticals, Inc. | Recruiting --> Completed | N=510 --> 214 | Trial completion date: Nov 2024 --> Apr 2026 | Trial primary completion date: Nov 2022 --> Apr 2026

GPR182+ PSCs could also predict the responses of colorectal cancer patients to certain drug treatments, such as rapamycin and midostaurin. Our findings map the epithelial heterogeneity in FAP and reveal that GPR182+ PSCs are crucial in driving heterogeneity and immune evasion. GPR182+ PSCs represent promising biomarkers for prognosis and drug responses, providing novel insights into FAP pathology and therapeutic development.

DPP4 expression was assessed by qPCR in 22Rv1 and C4-2 cells treated with dasatinib or midostaurin at IC50 concentrations. On the contrary, DPP4 expression in both 22Rv1 and C4-2 was reduced after treatment with midostarin (p < 0.05). Our study establishes DPP4 as a multifaceted pan-cancer biomarker with prognostic significance and immunotherapeutic implications, particularly in prostate cancer.

In this first real-world analysis of post-alloHCT FLT3-TKI maintenance in older adults, utilization was low and adherence was modest, although not impaired by age alone. Gilteritinib demonstrated the highest adherence and appeared to have favorable tolerability. Strategies to improve adherence and prospective data in older adults are needed to maximize the benefits of FLT3-TKI maintenance in this population.

Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.

Among them, compound 35 showed the most potent inhibition against FLT3-ITD (IC₅₀ = 3.16 ± 0.49 nM) and FLT3-WT (IC₅₀ = 294.7 ± 14.5 nM), comparable to the clinical reference midostaurin, with a ∼93-fold selectivity index...Mechanistic studies demonstrated that compound 35 effectively suppressed FLT3 phosphorylation and downstream STAT5, Akt, and Erk signaling, induced G2/M cell-cycle arrest, and triggered apoptosis in FLT3-ITD-positive AML cells. Taken together, these findings identify compound 35 as a potent and selective FLT3 inhibitor and establish a promising scaffold for the development of next-generation therapeutics against FLT3-driven leukemias.

P1, N=22, Recruiting, Richard Stone, MD | Trial completion date: Mar 2027 --> Mar 2028 | Trial primary completion date: Mar 2026 --> Mar 2027

In FLT3-ITD AML cell lines (MOLM13 and MV4-11), treatment with first- and second-generation FLT3i (midostaurin and quizartinib, respectively) induced autophagy. The combination of quizartinib and chloroquine demonstrated a synergistic effect in MV4-11QR cells and this effect was associated with greater inhibition of the FLT3 receptor compared to the monotherapies. Therefore, combining FLT3i with autophagy inhibition enhances the FLT3i antileukemic efficacy and overcomes pharmacological resistance.

All fit patients with FLT3m-AML must receive intensive chemotherapy plus a FLT3i (midostaurin or quizartinib) and be evaluated for allo-HSCT. For unfit patients, the current standard of HMA + venetoclax is considered suboptimal, making the search for alternative strategies imperative...In the R/R setting, retesting the FLT3 status is mandatory, and gilteritinib is the standard treatment, serving as a bridge-to-transplant and for post-HSCT maintenance. The integration of FLT3i has shifted FLT3m-AML into a more favorable intermediate prognostic category, enhancing the role of curative strategies like allo-HSCT. This consensus paper provides a structured evidence-based comprehensive guide, translating complex data into clear actionable clinical recommendations that minimize practice variability and ultimately optimize management for this high-risk population.

P2, N=22, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2029 --> May 2029 | Trial primary completion date: May 2027 --> Jan 2026