A promising MEK inhibitor in mice loses some luster in human trials

Generally, every time you get positive results for a new cancer drug from a preclinical study, the researchers herald the potential for humans and then wait and see if it can be taken into humans, which then offers a whole different set of challenges that will frequently reveal that the drug is dangerous or simply doesn't work.

In a twist on this theme, researchers at the University of Colorado Cancer Center have highlighted the problematic fate of one such next-gen cancer therapy, the MEK inhibitor TAK-733 at Takeda, as it made the leap from mouse and cell-line investigation and was tried in humans. The work was published in the journal Oncotarget.

TAK-733 works along the MAPK pathway that plays a role in cell growth and survival. If you work in animal research, you'll know where this is headed. The drug looked great in cell lines and had a distinct impact on 15 of 20 patient-derived tumors grown in mice. Researchers linked the drug with shrinkage in 9 different tumors.

Dr. Christopher Lieu, investigator at the CU Cancer Center

"The preclinical results for TAK-733 were fairly impressive. We had high hopes that TAK-733 could be a next-generation MEK inhibitor that might support or replace the use of current drugs," says Dr. Christopher Lieu, investigator at the CU Cancer Center and assistant professor of medical oncology at the University of Colorado School of Medicine.

The problem, he adds, is that once researchers began to study the drug in humans, they found that the drug was not absorbed in the same way as mice, providing lower bioavailability than what was needed to provide a consistently beneficial response among patients.

"It's not just the activity of a drug that matters, it's the safety and tolerability and bioavailability," Lieu says.

The scientist says he hasn't lost hope in TAK-733, looking forward to combination studies focused on colon cancer. But the drug offers a solid lesson in balancing scientists' preclinical expectations against actual clinical results. There are few straight and narrow paths between mouse and human studies.

- here's the release
- read the research article

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