Drug Information

Drug (ID: DG00429) and It's Reported Resistant Information

• Name: Lestaurtinib
• Synonyms: A 1544750; CEP 701; KT 5555; KT5555; SP 924; CEP-701; KT-5555; SPM-924; Lestaurtinib (USAN/INN)
• Indication:
  In total 3 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved (orphan drug); [1]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Phase 3; [1]
  Psoriasis [ICD-11: EA90]; Phase 2/3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Formula: C26H21N3O4
• IsoSMILES: C[C@@]12[C@](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)(CO)O
• InChI: 1S/C26H21N3O4/c1-25-26(32,12-30)10-18(33-25)28-16-8-4-2-6-13(16)20-21-15(11-27-24(21)31)19-14-7-3-5-9-17(14)29(25)23(19)22(20)28/h2-9,18,30,32H,10-12H2,1H3,(H,27,31)/t18-,25+,26+/m1/s1
• InChIKey: UIARLYUEJFELEN-LROUJFHJSA-N
• PubChem CID: 126565
• ChEBI ID: CHEBI:91471
• TTD Drug ID: D0V9WF
• DrugBank ID: DB06469

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835E
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Chromosome variation; FLT3/ITD (Internal tandem duplication )
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Streptothricin acetyltransferase (STA) [2]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: JAK-STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: MDA-H2774 cells; Ascites; Homo sapiens (Human); CVCL_0420
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: FT194 cells; Fallopian tube; Homo sapiens (Human); CVCL_UH58
• In Vitro Model: FT282 cells; Fallopian tube; Homo sapiens (Human); CVCL_A4AX
• Experiment for Molecule Alteration: RNA sequencing assay; RT-qPCR; Western blot assay
• Experiment for Drug Resistance: Proliferation assay; Cell cycle profiling assay; Apoptosis assay; Colony formation assay
• Mechanism Description: Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.

References

• Ref 1: FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017 Jun;16(6):991-1001. doi: 10.1158/1535-7163.MCT-16-0876.
• Ref 2: Lestaurtinib's antineoplastic activity converges on JAK/STAT signaling to inhibit treatment na?ve and therapy resistant forms ovarian cancer. NPJ Precis Oncol. 2025 Jul 11;9(1):236.