How novel combos could overcome resistance to targeted drugs in leukemia, solid tumors and more

cancer cell surrounded by killer T cells
In a study, blocking MEK and RAF promoted the expansion of cancer-killing T cells. (NIH)

Drugs that target cancer-causing genes have proven effective in many tumor types, but patients often become resistant to them. Combination therapies could be key to overcoming this problem, and two academic groups recently released promising preclinical research on two such combos.

A team at Cincinnati Children's Hospital Medical Center focused on resistance to mTOR inhibitors in patients with relapsed acute myeloid leukemia (AML). These drugs, which include rapamycin and several second- and third-generation mTOR inhibitors, are effective in many tumor types but have been disappointing in AML.

The researchers discovered that hemopoietic stem cells in bone marrow respond to the loss of mTOR by activating an alternate protein-signaling pathway that allows leukemia cells to escape treatment. Inhibiting three other genes by combining mTOR blockers with drugs that are already in clinical trials could counteract resistance, they reported in the journal Proceedings of the National Academy of Sciences.

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The researchers used a new mouse model to study what happens when mTOR is eliminated. They found that the production of stem cells in the bone marrow launches into overdrive, producing new blood cells that multiply using new signaling pathways.

From there, they used genetic analysis tools to determine that the new signaling pathways boost the expression of the gene c-Myc. Inhibiting two other genes, MNK and CDK9, might also counteract resistance to mTOR inhibitors, they suggested. Experimental drugs that inhibit the BET could act against c-Myc, and there are other experimental compounds that inhibit CDK9, they said.

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A team at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center focused in on the MAPK pathway, which is known to drive cancer. Drugs that target BRAF mutations hit this pathway and are effective in some patients with melanoma or lung cancer, but relapses are common.

The UCLA researchers found in preclinical studies that combining two small-molecule drugs that inhibit MEK and RAF suppresses the MAPK pathway. They believe the combination could hold promise in some aggressive subtypes of melanoma as well as lung, pancreatic and colon cancers, they reported in Cancer Discovery.

By studying patient tumors and mouse models, the researchers discovered that drugs blocking MEK and RAF proteins work against MAPK in two separate ways. First, they “lock” the two proteins together in a way that prevents growth-promoting signals. Second, they promote the expansion of cancer-killing T cells.

“The combination unexpectedly preserves killer T-cells inside the tumors, which allows them to hunt down drug-resistant tumor clones,” said co-senior author Gatien Moriceau, Ph.D., assistant adjunct professor at UCLA’s David Geffen School of Medicine, in a statement.

RAF and MEK inhibitors are in clinical trials in several tumor types, including non-small cell lung cancer and other solid tumors. Moriceau believes the new study justifies testing combinations of these drugs with medicines that inhibit the immune checkpoints PD-1 and PD-L1.