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Reversible TKI can be readily administered as a single agent, but response is complicated by induction of TKI resistance potentially due to selection of resistant clones. Acquired resistance to TKI occurs as a mechanism in more than 50% of cases within weeks of therapy onset and is generally clonal in origin, thus representing the best evidence of real-time tumor evolution. Relapse after allogeneic transplant suggests that acquired resistance mechanisms in vivo are clonal and not a transient effect of toxin treatment or chemotherapy. Not all mechanisms of resistance are equally difficult to target, as evidenced by the ability of N-RAS and BCL-2 to be inhibited by some, but not all, TKI.36,49,50 Moreover, combinations of TKI therapies are active in patients resistant to TKI therapy alone, suggesting that effective combinations of TKI therapy will need to target both tumor intrinsic and extrinsic mechanisms of TKI resistance. Additionally, tumors with inherent TKI resistance due to mutations in Ras and BCL-2 may be vulnerable to inhibition of PI3K and ERBB4 signaling.

We are currently attempting to target the core oncogenic NOTCH1 mutation with small molecule inhibitors alone or in combination with TKI therapy. We are also developing NOTCH1-targeted clinical cell therapy protocols using engineered T-ALL cells infected with lentiviruses expressing an EGFP-based biosensor for monitoring activation of NOTCH1 signaling in the tumor environments generated in xenograft mouse models. This approach provides a cell-based platform for confirming NOTCH1 inhibition in preclinical settings.

Treatment of T-ALL with direct inhibitors of NOTCH1 is relatively straightforward given the documented ability of NOTCH1-activating mutations to contribute to the etiology of the malignancy. Inhibitors of the NOTCH1 transduction pathway including GSIs, ibrutinib, inhibitors of the endogenous NOTCH signaling pathway including DAPT, and NOTCH1 antibodies are currently in use or in active development.26,27,32,33,53,54 Currently, the single-agent activity of GSIs has been disappointing, and there is no proven standard-of-care regimen for TKI resistant T-ALL. d2c66b5586