Secondary mutations as mediators of resistance to targeted therapy in leukemia

Abstract

The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

“…A common resistance mechanism found with many of the tyrosine kinase inhibitors is the acquisition of molecular variants ranging from single nucleotide changes to intragenic deletions (27). Specifically in the PMT family, which includes DOT1L and EZH2, publications by Gibaja and colleagues and Baker and colleagues highlighted secondary mutations in both wild-type and mutant EZH2 alleles leading to resistance of specific small molecule PMT inhibitors in preclinical in vitro models (35,36).…”

“…Despite advances in understanding the molecular mechanisms of disease and implementation of targeted therapies, a common limiting factor to sustained efficacy in cancer patients is the emergence of resistant clones (27,28). Resistance has been reported to occur through multiple mechanisms such as transformation of the drug target through genetic variation (indels or single base modifications), overexpression, and alternative signal transduction (28).…”

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

“…Because HSP90 inhibitors target several important BCR signaling effectors at once, they might also become a valuable tool in the context of kinase inhibitor resistance, which is driven by mutations in the target kinase itself or bypass mechanisms through other cell survival promoting kinases. [33][34][35] In summary, we identified and characterized HSP90 inhibitors as an efficient tool to induce apoptosis in BL cells, providing a basis for the development of novel and more specific therapeutic strategies for BL patients.…”

An update of current treatments for adult acute myeloid leukemia

“…65 Selection of FLT3-resistant mutants has been a general phenomenon observed in most early trials with first-or secondgeneration inhibitors. 66 An overview of novel promising FLT3 inhibitors is presented elsewhere in this Review Series.…”