Abstract
Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from T-cell committed lymphoblasts, with a diffuse invasion of bone marrow and peripheral blood [1]
Because T-ALL lymphoblasts are morphologically indistinguishable from B-ALL (B-cell acute lymphoblastic leukemia), immunophenotypic characterization defines each stage of intrathymic differentiation by the expression pattern of cluster of differentiation (CD) antigens
In SUPT1 and P12-ICHIKAWA T-ALL cells, CI1040 reduced downstream activation of mammalian target of rapamycin (mTOR) and prevented BIM phosphorylation by ERK, restoring steroid sensitivity [29]. These results suggest that the potent cytotoxic effects of inhibiting both phosphatidylinositol-3 kinase (PI3K)-AKT-mTOR and RAS-MAPK-ERK may increase steroid responsiveness, and should be investigated further, since they may represent an effective treatment in a subset of aggressive T-ALL
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from T-cell committed lymphoblasts, with a diffuse invasion of bone marrow and peripheral blood [1]. Immature thymocytes that maintain the ability to differentiate into both T-cell and myeloid lineage are characterized by the lack of CD8, CD4, CD1a, and CD5 (weak) expression, and the presence of at least one myeloid/stem cell antigen (CD34, CD33, CD13, CD11b, CD65, and/or HLA-DR) (Figure 1) This pattern identifies a subtype of T-cell leukemia, early T precursor (ETP) ALL, which accounts for 15% of pediatric and 35% of adult cases [4,5]. Advances in genetic characterization have paved the way for the discovery of targeted therapies, with the combined goal to reduce the life-long off-target toxicities seen with the chemotherapeutic regimens, and the increase of complete remission (CR) Despite these efforts, resistance to standard chemotherapy, glucocorticoids, or new drugs remains the major hurdle to achieve meaningful progress in R/R T-ALL.
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