Mechanisms of resistance to targeted therapies for relapsed or refractory acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive disease of clonal hematopoiesis with a high rate of relapse and refractory disease despite intensive therapy. Traditionally, relapsed or refractory AML has increased therapeutic resistance and poor long-term survival. In recent years, advancements in the mechanistic understanding of leukemogenesis have allowed for the development of targeted therapies. These therapies offer novel alternatives to intensive chemotherapy and have prolonged survival in relapsed or refractory AML. Unfortunately, a significant portion of patients do not respond to these therapies and relapse occurs in most patients who initially responded. This review focuses on the mechanisms of resistance to targeted therapies in relapsed or refractory AML.

Figure 1:

Mechanisms of Resistance to tyrosine kinase inhibitors in FLT3 mutated AML. A. Altered signaling in previously untreated newly diagnosed or relapsed AML with mutated FLT3. B. Decreased FLT3 mediated signaling and induction of apoptosis with tyrosine kinase inhibitor treatment in sensitive cells carrying FLT3 mutations. C. Mutations associated with resistance in relapsed refractory FLT3 mutated AML treated with tyrosine kinase inhibitors. Star indicates reported mutations. D. Altered cellular regulatory processes that allow for improved survival in treatment resistant cell lines or relapsed or refractory AML samples. Increased survival can be mediated through upregulation of alternative cell surface receptors or ligand-mediated signaling (1), expression of anti-apoptotic proteins (2), and STAT5 activation by mutated FLT3 in the endoplasmic reticulum (ER) (3).

Figure 2:

Mitochondrial regulation relapsed or refractory AML cells. A. Venetoclax inhibits anti-apoptotic protein BCL-2, which leads to increased cytochrome C release and induction of intrinsic apoptosis in sensitive cells. B. In resistant relapsed or refractory AML cells, increased expression of anti-apoptotic proteins (MCL1, BCL-xL) leads to a decrease in intrinsic apoptosis. C. In relapsed or refractory AML cells resistant to venetoclax, increased oxidative phosphorylation can be supported by amino acid uptake, beta oxidation of fatty acids, and nicotinamide adenine dinucleotide (NAD⁺) synthesis.