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Resistance to targeted therapies in acute myeloid leukemia.

ABSTRACT: The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment.

SUBMITTER: Mecklenbrauck R

PROVIDER: S-EPMC9898349 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Resistance to targeted therapies in acute myeloid leukemia.

Mecklenbrauck Rabea R Heuser Michael M

Clinical & experimental metastasis 20221101 1

The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by ...[more]

PMID: 36318439

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Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.

Dataset Information

Resistance to targeted therapies in acute myeloid leukemia.

Publications

Resistance to targeted therapies in acute myeloid leukemia.

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