Protein May Play a Role in Treatment-Resistant Lung, Breast Cancers

Findings from a recent study suggest that blocking a protein in cancer cells may reverse, and even prevent, treatment-resistant lung and breast cancers.

The protein, Ran-GTP, causes cancer cells to become resistant to the chemotherapy drug gefitinib, which is a first-line treatment for lung cancer. According to a study published by Oncotarget, this protein may also be able to predict the prognosis in patients with breast cancer.

The study examined the link between Ran-GTP and a protein linked to multiple cancers, c-Met. High levels of c-Met have been shown to cause chemotherapy resistance in breast and lung cancers.

Currently, there are clinical trials testing the efficacy of c-Met inhibitors in patients with lung cancer. Scientists in the study said targeting Ran-GTP may be a better approach.

“Much is known about the activity of c-Met and its impact on cancer, but our research is looking at things a step earlier, by focusing on the protein that regulates c-Met — Ran-GTP,” said lead researcher Mohamed El-Tanani, D’Sc, MPhil, PhD. “c-Met needs Ran-GTP to function, and in particular needs very high levels when it becomes over-expressed or mutates – as is the case in cancers. By blocking Ran-GTP, we were able to both undo the resistance caused by c-Met and prevent that resistance occurring. This shows that Ran-GTP could be a good therapeutic target for cancer treatment, particularly in lung and breast cancer.”

In the study, scientists analyzed tissue samples from 247 patients with breast cancer, and discovered that patients with a poor prognosis had high levels of c-Met and Ran-GTP. It was previously thought that high levels of c-Met in patients with breast cancer was associated with a higher mortality rate.

However, these new findings suggest that Ran-GTP may play a larger role in prognosis and treatment resistance than previously thought.

“This finding emphasizes how the role of Ran-GTP, rather than the expression of c-Met alone, seems to be key to the progression of cancer,” said Dr El-Tanani. “Even when c-Met was high and Ran was low, a patient’s prognosis was much better. This means we might be able to use Ran levels to stratify patients to determine the most appropriate treatment, intervening with more aggressive treatments only in patients with high levels of both proteins.”

The scientists are currently exploring different drug compounds with the ability to inhibit Ran-GTP expression to replicate their experiment.

“We’ve already screened millions of potential compounds that have the potential to inhibit Ran to find the most potent one in vitro and in vivo model systems as a preclinical validation,” said Dr El-Tanani. “We now have 2 very strong candidates ready to move forward into clinical trials.”

A candidate for the clinical trials is an existing drug that has been pre-clinically validated in breast and lung cancers, according to the study. Since the drug is known to be safe, it can move right to phase 2 trials.

The second candidate is a peptide that has been tested in animal models, the scientists reported.

“It’s been a long road to get to this stage, but we’re very excited about the clinical potential for Ran-GTP inhibitors,” Dr El-Tanani concluded. “It would be wonderful to see new treatments that block this protein enter trials, hopefully prove their effectiveness in treating cancer and eventually reach the clinic.”