Blocking C-FOS and DUSP1 Signaling Proteins Shows Promise Against Treatment-Resistant Cancers

Published March 20, 2017
Nature Medicine

Chemotherapy plus treatments blocking two key signaling proteins effectively eliminated human leukemia in mouse models, according to a breakthrough study led by Cincinnati Children’s researchers.

Their findings suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant cancers. These include acute myeloid leukemia fueled by the gene FLT3, lung cancers driven by the genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML).

“We think that within the next five years our data will change the way people think about cancer development and targeted therapy,” says lead investigator Mohammad Azam, PhD. “This study identifies a potential Achilles’ heel of kinase-driven cancers.”

Azam and colleagues conducted extensive gene expression analysis to find a weak spot in cancer development: a signaling node formed by c-Fos and Dusp1.

CML is driven by the enzyme tyrosine kinase. Analysis of treatment-resistant human CML cells revealed high levels of c-Fos and Dusp1. These proteins appear to increase the toxic threshold needed to kill cancer cells, allowing some to survive traditional chemotherapy.

The research team tested various treatment combinations against CML and B-cell acute lymphoblastic leukemia (B-ALL). For CML, applying the chemotherapy drug imatinib along with molecular inhibitors of c-Fos and Dusp1 cured 90 percent of treated mice. However, treatment with just the protein inhibitors proved sufficient to eradicate B-ALL in mouse models.

The next steps for this research include further steps required to prepare for human clinical trials. Investigators also plan to evaluate c-Fos and Dusp1 inhibitors as potential treatment for other kinase-fueled cancers.