Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia

Abstract

Relapse and refractory T cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 inhibitors and the general tyrosine kinase-inhibitor, dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.

Notch Partners in the Long Journey of T-ALL Pathogenesis

“…Moreover, NOTCH1 regulates the phosphorylation of multiple signaling proteins of the mTOR pathway through a PI3K/AKT-independent but MYC-dependent mechanism [ 212 ]. mTOR is an essential regulator of T-ALL cell growth, and its inhibition has been demonstrated to have anti-leukemic effects either alone or in combination with other drugs [ 106 , 213 , 214 , 215 , 216 , 217 , 218 , 219 ]. Notably, dual inhibition of NOTCH1 and mTOR signaling was proved to act synergistically by blocking T-ALL proliferation in vitro [ 106 ].…”

The pathogenesis and development of targeted drugs in acute T lymphoblastic leukaemia

“…Lck inhibitors, such as dasatinib and SJ11646, showed efficacy against T‐acute lymphoblastic leukaemia in preclinical studies and in patients with T‐acute lymphoblastic leukaemia (Hu et al, 2022). Recent important studies have shown that the combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T‐acute lymphoblastic leukaemias (Laukkanen et al, 2022). Together, Lck inhibitors are promising therapeutic agents in T‐acute lymphoblastic leukaemia and other cancers.…”

New insights into the Lck-NF-κB signaling pathway

“…Upon dasatinib treatment, phosphorylation of the Lck substrate Zap-70 decreased, and secretion of cytokines including IL-2, TNF-α, and IFN-γ was also rapidly abolished (Lee et al, 2010;Leclercq et al, 2021). Dasatinib is also indicated for T-ALL treatment through inhibiting Lck function by interrupting downstream propagation of TCR signals, thus leading to suppression of cell proliferation (Laukkanen et al, 2022). In addition, Han et al (2014) found that dasatinib could significantly inhibit migration of glioma stem cells.…”