Surface pTα expression predicts LCK activation and preclinical synergy of LCK and JAK coinhibition in adult T-ALL

Abstract

Refractory and/or relapsing T-cell acute lymphoblastic leukemia (T-ALL) remains a major therapeutic challenge. The pre-T-cell receptor (TCR) pathway has recently emerged as a therapeutic target via LCK inhibition in this context. However, there is a need for simple and quickly assessable biomarkers to predict sensitivity to LCK inhibitors. Moreover, targeting LCK alone by tyrosine kinase inhibitors, such as dasatinib, often results in transient clinical responses, emphasizing the need for efficient combination strategies. Here, we assessed pre-TCR α chain (pTα) surface expression by flow cytometry in a unique series of 50 adult T-ALL patient-derived xenografts (PDXs). We show that cases displaying a cortical phenotype often express high levels of surface pTα (pre-TCR+ T-ALL) and that the latter associates with LCK activation. Furthermore, we show that ectopic interleukin-7 receptor (IL-7R) expression can rescue pre-TCR+ T-ALL from dasatinib cytotoxicity (5 PDXs). We tested whether coinhibition of pre-TCR and IL-7R signaling pathways could be synergetic in pre-TCR+ IL-7R+ T-ALL (11 PDXs). Combination of JAK inhibitors, ruxolitinib or tofacitinib, with dasatinib elicited strong and specific synergy in IL-7R+ pre-TCR+ T-ALL in vitro, including in the relapse setting (4 of 28 patient-derived primary samples). Using 3 adult-PDX models, we show that in vivo treatment with this combination significantly delayed leukemic progression and prolonged survival compared with either monotherapy. This preclinical study thus proposes the use of pTα as a biomarker of LCK-inhibitor sensitivity in T-ALL, and suggests that dual targeting of IL-7R and pre-TCR signaling pathways may be a relevant therapeutic strategy in a substantial proportion of adult T-ALL.