The mechanistic target of
rapamycin (mTOR) is a
serine/threonine kinase whose activity contributes to
leukemia proliferation and survival. Compounds targeting the mTOR active site inhibit
rapamycin-resistant functions and have enhanced anticancer activity in mouse models.
MLN0128 (formerly known as
INK128) is a novel, orally active mTOR
kinase inhibitor currently in clinical development. Here, we evaluated
MLN0128 in preclinical models of B-cell
acute lymphoblastic leukemia (B-ALL).
MLN0128 suppressed proliferation of B-ALL cell lines in vitro and reduced colony formation by primary human
leukemia cells from adult and pediatric B-ALL patients.
MLN0128 also boosted the efficacy of
dasatinib (DA) in
Philadelphia Chromosome-positive (Ph+) specimens. In a syngeneic mouse model of lymphoid BCR-ABL+ disease, daily oral dosing of
MLN0128 rapidly cleared leukemic outgrowth. In primary xenografts of Ph+ B-ALL specimens,
MLN0128 significantly enhanced the efficacy of DA. In non-Ph B-ALL xenografts, single agent
MLN0128 had a
cytostatic effect that was most pronounced in mice with low disease burden. In all in vivo models,
MLN0128 was well tolerated and did not suppress endogenous bone marrow proliferation. These findings support the rationale for clinical testing of
MLN0128 in both adult and pediatric B-ALL and provide insight towards optimizing therapeutic efficacy of mTOR
kinase inhibitors.