Kinase oncoproteins and growth factors both activate the proto-oncogene c-FOS and DUSP1, allowing the persistence of residual leukemia cell populations despite tyrosine kinase inhibitor (TKI) therapy, according to findings from a new preclinical study published in Nature Medicine.
Leukemia stem cells appear to become addicted to elevated c-FOS and DUSP1 during TKI therapy, which could lead to intrinsic TKI resistance and eventual relapse, they concluded.
“Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles’ heel of kinase-driven cancers,” reported study co-author Mohammad Azam, PhD, Cincinnati Children’s Hospital Medical Center in Cincinnati, and colleagues. “
TKI therapy is not curative for cancer, the authors noted; persisting cancer cell populations, known as minimal residual disease (MRD), eventually lead to relapse.
The research team experimentally manipulated expression of c-FOS and DUSP1 in animal models, in an effort to overcome this intrinsic resistance and destroy residual tumor cells after TKI therapy.
“Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML),” they reported. “Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells.”
They subsequently demonstrated that growth factor signaling similarly induces Fos and DUSP1 expression and underlies TKI resistance in animal models of other leukemias, such as BCR-ABL-induced B-cell acute lymphoblastic leukemia (B-ALL).
The team also showed that higher FOS and DUSP1 levels induced anti-apoptosis gene expression, and that these and pro-survival genes’ expression could be suppressed with FOS and DUSP1 inhibitors.
“Taken together, these data provide evidence that higher levels of Fos and Dusp1 are required to maintain growth factor-induced expression of pro-survival and anti-apoptotic genes,” they concluded.