LAM-003, a new drug for treatment of tyrosine kinase inhibitor-resistant FLT3-ITD-positive AML
- PMID: 31751472
- PMCID: PMC6880894
- DOI: 10.1182/bloodadvances.2019001068
LAM-003, a new drug for treatment of tyrosine kinase inhibitor-resistant FLT3-ITD-positive AML
Abstract
Acute myeloid leukemias (AML) harboring a constitutively active internal tandem duplication (ITD) mutation in the FMS-like kinase tyrosine kinase (FLT3) receptor are associated with poor patient prognosis. Despite initial clinical responses to FLT3 kinase inhibitors, patients eventually relapse. Mechanisms of resistance include the acquisition of secondary FLT3 mutations and protective stromal signaling within the bone marrow niche. Here we show that LAM-003, a prodrug of the heat shock protein 90 inhibitor LAM-003A, has cytotoxic activity against AML cell lines and primary samples harboring FLT3-ITD. LAM-003 regressed tumors in an MV-4-11 xenograft mouse model and extended survival in a MOLM-13 systemic model. LAM-003 displayed synergistic activity with chemotherapeutic drugs and FLT3 inhibitors, with the most robust synergy being obtained with venetoclax, a BCL-2 inhibitor. This finding was verified in a MOLM-13 systemic survival model in which the combination significantly prolonged survival compared with the single agents. Importantly, LAM-003 exhibited equipotent activity against FLT3 inhibitor-resistant mutants of FLT3, such as D835 or F691, in cytotoxic and FLT3 degradation assays. LAM-003 also retained potency in AML cells grown in stromal-conditioned media that were resistant to FLT3 inhibitors. Lastly, a genome-wide CRISPR screen revealed epigenetic regulators, including KDM6A, as determinants of LAM-003 sensitivity in AML cell lines, leading to the discovery of synergy with an EZH2 inhibitor. Collectively, these preclinical findings support the use of LAM-003 in FLT3-ITD patients with AML who no longer respond to FLT3 inhibitor therapy either as a single agent or in combination with drugs known to be active in AML.
© 2019 by The American Society of Hematology.
Conflict of interest statement
Conflict-of-interest disclosure: N.B., S.L., S.G., J.E.G., P.B., M.H., P.R.Y., and H.L. are employees at AI Therapeutics. T.X. is on the AI Therapeutics advisory board. J.R. is a Director of AI Therapeutics. AI Therapeutics is the owner of LAM-003/LAM-003A patents. The remaining authors declare no competing financial interests.
Figures
![None](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068absf1.gif)
![Figure 1.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068f1.gif)
![Figure 2.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068f2.gif)
![Figure 3.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068f3.gif)
![Figure 4.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068f4.gif)
![Figure 5.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068f5.gif)
![Figure 6.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6880894/bin/advancesADV2019001068f6.gif)
Similar articles
-
Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia.Blood. 2013 Nov 21;122(22):3607-15. doi: 10.1182/blood-2013-07-513044. Epub 2013 Sep 17. Blood. 2013. PMID: 24046014 Free PMC article.
-
Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies.Clin Cancer Res. 2014 May 1;20(9):2363-74. doi: 10.1158/1078-0432.CCR-13-2052. Epub 2014 Mar 11. Clin Cancer Res. 2014. PMID: 24619500 Free PMC article.
-
A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia.J Hematol Oncol. 2021 Jul 3;14(1):105. doi: 10.1186/s13045-021-01098-y. J Hematol Oncol. 2021. PMID: 34217323 Free PMC article.
-
The Future of Targeting FLT3 Activation in AML.Curr Hematol Malig Rep. 2017 Jun;12(3):153-167. doi: 10.1007/s11899-017-0381-2. Curr Hematol Malig Rep. 2017. PMID: 28421420 Review.
-
Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment.Hematol Oncol Clin North Am. 2017 Aug;31(4):681-692. doi: 10.1016/j.hoc.2017.04.005. Epub 2017 May 18. Hematol Oncol Clin North Am. 2017. PMID: 28673395 Free PMC article. Review.
Cited by
-
CRISPR screening in hematology research: from bulk to single-cell level.J Hematol Oncol. 2023 Oct 24;16(1):107. doi: 10.1186/s13045-023-01495-5. J Hematol Oncol. 2023. PMID: 37875911 Free PMC article. Review.
-
Phytochemicals and bioactive compounds effective against acute myeloid leukemia: A systematic review.Food Sci Nutr. 2023 May 15;11(7):4191-4210. doi: 10.1002/fsn3.3420. eCollection 2023 Jul. Food Sci Nutr. 2023. PMID: 37457145 Free PMC article.
-
NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia.Cell Death Discov. 2023 Jun 30;9(1):208. doi: 10.1038/s41420-023-01528-5. Cell Death Discov. 2023. PMID: 37391442 Free PMC article. Review.
-
Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells.Blood. 2023 Sep 21;142(12):1056-1070. doi: 10.1182/blood.2022019047. Blood. 2023. PMID: 37339579
-
Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.Cancers (Basel). 2022 Sep 2;14(17):4315. doi: 10.3390/cancers14174315. Cancers (Basel). 2022. PMID: 36077850 Free PMC article. Review.
References
-
- Carow CE, Levenstein M, Kaufmann SH, et al. . Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87(3):1089-1096. - PubMed
-
- Kiyoi H, Naoe T, Nakano Y, et al. . Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93(9):3074-3080. - PubMed
-
- Fröhling S, Schlenk RF, Breitruck J, et al. ; AML Study Group Ulm. Acute myeloid leukemia . Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372-4380. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous