Novel Therapeutic Target Shows Promise in Treatment-Resistant Leukemia

Blocking 2 signaling proteins that allow cancer cells to become treatment-resistant, plus chemotherapy, can eliminate human leukemia in mouse models.

Findings from a study published in Nature Medicine suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy could cure several types of treatment-resistant, kinase-drive leukemia and solid tumor cancers.

“We think that within the next 5 years our data will change the way people think about cancer development and targeted therapy,” said lead investigator Mohammad Azam, PhD. “This study identifies a potential Achilles heel of kinase-driven cancers and what we propose is intended to be curative, not just treatment.”

The investigators found that the Achilles heel—or weak spot—is a signaling node that is apparently required to generate cancer cells in leukemia and solid tumors, and is formed by C-Fos and Dusp1 signaling proteins.

For the study, investigators conducted a global gene expression analysis of mouse leukemia cells and human chronic myeloid leukemia (CML) cells donated by patients. The results of the analysis showed that human CML cells had extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy-resistant cells.

In the CML models, the investigators showed that signaling from tyrosine kinase and growth factor proteins that support cell expansion converge to dramatically increase levels of c-Fos and Dusp1 in cancer cells.

When working together, the molecules maintained the survival of cancer stem cells and minimal residual disease. The dormant cells rekindle the disease by acquiring genetic mutations and chemotherapy.

Dusp1 and c-Fos support the survival of cancer stem cells by increasing the toxic threshold needed to kill them, meaning conventional imatinib chemotherapy cannot eliminate the residual cancer stem cells.

Once the investigators identified c-Fos and Dusp1, they tested different treatment combinations on CML mouse models, human CML cells, and mice transplanted with human leukemia cells. Treatments were also tested on B-cell acute lymphoblastic leukemia (B-ALL).

The following treatment combinations were solo therapy with imatinib alone, solo treatment with inhibitors of c-Fos and Dusp1, and treatment with all 3 combined.

The results of the study showed that, initially, imatinib monotherapy stopped CML progression, but the cancer relapsed with the continued presence of residual disease cells. Treatment with c-FOS and Dusp1 inhibitors alone significantly slowed CML progression and prolonged survival in a majority of mice, but was not curative.

One month of treatment with c-FOS and Dusp1 inhibitors plus imatinib cured 90% of mice with CML, with no signs of residual disease cells.

Although the findings show promise, the authors stress that more research needs to be done before the treatment strategy can be tested in clinical trials. Currently, investigators are testing c-Fos and Dusp1 as treatment targets for kinase-fueled cancers, which includes certain types of lung cancer, breast cancers, and acute forms of leukemia.