Secondary mutations as mediators of resistance to targeted therapy in leukemia.
Level 5 - mechanism / opinion, no new human data
Narrative review synthesizing mechanisms of targeted therapy resistance without systematic review methodology or new human data
PubMed 25795921 · doi:10.1182/blood-2014-10-605808
What was done
This paper reviewed molecular mechanisms of acquired resistance to small-molecule targeted therapies in acute and chronic leukemias, focusing on secondary point mutations in kinase domains (such as FLT3, BTK, and BCR-ABL) and nonmutational bypass pathways.
What was found
The abstract reports no numerical data. It notes that secondary point mutations in kinase domains (specifically ATP-binding sites and activation loops) represent a primary mode of acquired resistance to targeted agents such as FLT3 inhibitors in acute myeloid leukemia, ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and ABT-199 in lymphoma. Second-generation inhibitors and combination regimens are highlighted as strategies to overcome this resistance.
Why it matters
Synthesizing recurring resistance mechanisms helps guide the design of next-generation kinase inhibitors and rational combination therapies to prevent or overcome treatment failure in hematologic malignancies.
Limits
As a narrative review, no search criteria, study selection parameters, sample sizes, or quantitative outcome metrics are reported in the abstract.
Cited by
- supports Cancer cells frequently evolve resistance to targeted molecular therapies through secondary genetic mutations, analogous to bacterial antibiotic resistance.