Complementary inhibition of tyrosine and SRC kinases implement dual SRC/ABL inhibitor effects in chronic myeloid leukemia (CML). Here, we show that one such inhibitor, SKI-606, induces persistent Cdk2 inactivation leading to growth arrest of BCR-ABL-expressing cells either IM-sensitive or driven to IM-resistance by other events than gene overexpression and point mutations. Inhibition of Akt serine/threonine kinase, a phosphatidylinositol 3 kinase (PI-3k) target that integrates p210 TK signaling with membrane-associated SRC kinases, is a central component of restored expression and subcellular redistribution of Cdk2 regulatory signals (p21 and p27 and Cdc25A phosphatase) in response to SKI-606. The putative roles of growth factor (namely IL-3) autocrine loop in BCR-ABL-expressing progenitor progression towards a drug-resistant phenotype are discussed.