Contact Us marketing@medicilon.com
CN
×
Close Button
Medicilon's News information
News information

Overcoming Resistance to a Standard Chemotherapy Drug

2018-07-24
|
Page View:

Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works.  Scientists at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors and cancer cell lines resistant to cisplatin, along with an experimental drug that targets that enzyme. Their study (“MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation”) appears in Cancer Cell.

“Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPKpathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome,” write the investigators.

Overcoming Resistance to a Standard Chemotherapy Drug

“Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models.”

Cisplatin is a DNA-damaging agent used in standard treatment for lung, head and neck, ovarian, and testicular cancers. Sumin Kang, Ph.D., assistant professor, department of hematology and medical oncology, Emory University School of Medicine and a Robbins Scholar pilot grant recipient at Winship, and colleagues at Winship decided to look for enzymes whose activity was necessary for cancer cells to withstand cisplatin treatment. They chose kinases and found that in combination with a sub-lethal amount of cisplatin, knocking down the activity of the kinase MAST1 kills a cell. But how does that combination work?

“We tested every type of drug resistance mechanism,” says Dr. Kang. “It seems to be ‘post target.’ That means it’s not related to the cells getting rid of the drug faster. And it doesn’t work on other agents that damage DNA, so it’s not related to enhanced repair.”

Instead, MAST1 seems to substitute for the activation of survival enzymes, cRaf and MEK1, which cisplatin interferes with. Cisplatin was known to unleash reactive oxygen species within the cell, but the interaction between cisplatin and the survival enzymes had not been observed before, Dr. Kang says. Levels of MAST1 seem to account for cisplatin resistance in a survey of cancer cell lines and primary human tumor samples.

The next step was to look for compounds that might inhibit MAST1. Dr. Kang’s team found one in lestaurtinib, a kinase inhibitor that has already been in clinical trials for several types of cancer, such as acute myelogenous leukemia. It was a surprise because lestaurtinib was thought to inhibit a different type of kinase (tyrosine kinases) than MAST1.

“It opens up several possibilities, such as lestaurtinib, and other inhibitors,” Dr. Kang says. “We think targeting MAST1 would be better than MEK1 because removing MAST1 doesn’t have much toxic effect on cells by itself.”

Potentially, such a combination could allow the dose of cisplatin to be reduced by several-fold, reducing side effects for patients, she adds.

In animal models with implanted tumors, cisplatin could be combined with lestaurtinib against several cancer cell types: head and neck squamous cell, lung cancer, ovarian, and cervical carcinoma.

“MAST1-targeted therapy would be more beneficial to patients with advanced cancers or patients who received platinum-based therapy but recurred, in part, due to the induction of MAST1 during the treatment. Future pharmacokinetics and toxicity studies, as well as clinical trials, are warranted,” note the scientists.

Share:
Return
Relevant newsRelevant news