Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia

Abstract

T-cell Acute Lymphoblastic Leukemia (T-ALL) is frequently characterized by glucocorticoid (GC) resistance, which is associated with inferior outcomes, thus highlighting the need for novel therapeutic approaches for GC resistant T-ALL. The pTCR/TCR signaling pathways play a critical role in cell fate decisions during physiological thymocyte development, with an interplay between TCR and glucocorticoid receptor (GR) signaling determining the T-lymphocyte selection process. We performed an shRNA screen in vitro and in vivo in T-ALL cell lines and patient derived xenograft (PDX) samples to identify vulnerabilities in the pTCR/TCR pathway and identified a critical role for the kinase LCK in cell proliferation. LCK knockdown or inhibition with dasatinib (DAS) caused cell cycle arrest. Combination of DAS with dexamethasone (DEX) resulted in significant drug synergy leading to cell death. The efficacy of this drug combination was underscored in a randomized phase II-like murine trial, recapitulating an early phase human clinical trial. T-ALL expansion in immunocompromised mice was significantly impaired using this drug combination, relative to mice receiving control vehicle or single drug treatment, highlighting the immediate clinical relevance of this drug combination for high risk T-ALL patients. Our results thus provide a strategy to improve the efficacy of current chemotherapy platforms and circumvent GC resistance.

Ameliorative impacts ofAllium cepa Linnaeusaqueous extract against testicular damage induced by dexamethasone

“…Glucocorticoids are used medicinally but with many negative and disease‐pathogenic side effects (Hashemitabar Mahmoud, 2009). Their physiological and biochemical effects on inflammation, immunity, metabolism and IL‐1β suppression (Kanda, Hirose, Noda, Murata, & Ishida, 2020), and apoptosis in lymphoid malignancies (Shi et al, 2020), are supported by the present study. One synthetic glucocorticoid, dexamethasone, is a common anti‐inflammatory used to treat asthma, allergic reactions and other immune‐mediated diseases and is also a chemotherapeutic agent (J. Liu et al., 2020).…”

“…Glucocorticoids have many negative and disease‐pathogenic side effects (Mahmoud et al., 2009). Glucocorticoids have physiological and biochemical effects on inflammation, immunity, metabolism and IL‐1β suppression, and apoptosis in lymphoid malignancies (Shi et al, 2020). Dexamethasone affects testis homeostasis, induces apoptosis in testicular germ cells and causes spermatogenesis defects such as histopathologic and morphometrical changes, alteration in the number of sperm head and maturation arrest in mice (Khorsandi et al., 2012).…”

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

“…Interestingly, in 2017, Frismantas and colleagues identified a subgroup of patients with T-ALL who are highly sensitive to dasatinib treatment in vitro despite the absence of ABL1 aberrations, suggesting a role for the SRC kinase as a putative novel target for therapy (66). Other studies proposed the lymphocytic-specific kinase LCK, which is often highly expressed in T-ALL, as a prime dasatinib target in T-ALL (67,68). Based on these preclinical data, patients presenting high SRC phosphorylation and/or increased LCK expression could potentially benefit from dasatinib treatment.…”

The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia

“…55,56 Encouragingly, synergy between small molecule inhibitors and dexamethasone has been shown to overcome glucocorticoid resistance in T-ALL. [57][58][59][60] Notably, several mutations (NOTCH1, FLT3, PTEN) were 'lost' at relapse, indicating they might represent non-founder or subclonal mutations. 15,30,61 This underlined our previous data, which highlighted at single cell level that NOTCH1 and PTEN mutations were subclonal and demonstrated convergent evolution.…”