According to a study conducted by a multidisciplinary team at Weill Cornell Medicine, a new protein variant underpins the ability of gastric cancers to resist an otherwise effective family of chemotherapy drugs. The findings point to a treatment strategy that could improve the prognoses of many cancer patients.
The study, published in Developmental Cell, combined clinical knowledge, laboratory experiments, and sophisticated computational analysis to determine how some tumor cells resist taxanes, a class of chemotherapy drugs. Taxanes work by interfering with proteins that form the cell’s internal skeleton, but a variant protein known as CLIP-170S allows cancer cells to avoid this interference.
“We identified a novel variant that is clinically prevalent, expressed in more than 60% of patients with gastric cancer, and operates via a mechanism distinct from previously discovered ones,” said co-senior author Dr. Paraskevi Giannakakou, professor of pharmacology in medicine, director of research in the Division of Hematology and Medical Oncology, and associate director for education in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Taxanes, which are based on compounds discovered in yew trees, are first-line treatments for a variety of cancers. Unfortunately, taxane-resistant cells frequently develop and survive treatment, leaving patients with few options and a poor prognosis. The problem is particularly severe in gastric cancer.
Most patients with gastric cancer live for less than a year, and if we could figure out a way to make the taxanes more effective, we could have a bigger impact on patients. A new protein variant underpins the ability of gastric cancers to resist an otherwise effective family of chemotherapy drugs.
Dr. Manish Shah
“Most patients with gastric cancer live for less than a year, and if we could figure out a way to make the taxanes more effective, we could have a bigger impact on patients,” said co-senior author Dr. Manish Shah, director of the Gastrointestinal Oncology Program and chief of the Solid Tumor Oncology Service in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Taxane-resistant tumors develop in about 80% of gastric cancer patients, he claims.
While years of research have revealed numerous ways for cancer cells to resist taxane-mediated killing, the findings have had little impact on clinical outcomes. “Everyone is trying to understand the mechanisms of taxane resistance, but nothing is helping patients clinically; none of the resistance mechanisms identified in the lab has had a clinical impact,” Dr. Giannakakou explained.
Dr. Shah approached Dr. Giannakakou with a reanalysis he’d done on data from the clinical trial that led to the FDA’s approval of taxanes for the treatment of patients with gastric cancer. The study discovered a subset of gastric cancer patients who did not benefit from taxane treatment at all, implying that their tumors were drug-resistant even before they were exposed to the compound.
The researchers compared cells derived from taxane-resistant tumors to those derived from taxane-sensitive tumors, working with a multi-institutional team of collaborators. They discovered that the taxane-resistant cells possessed a variant form of a protein known as CLIP-170, which normally aids in the function of the cell’s cytoskeleton.
Next, the team enlisted the aid of computational biologists to look for ways to overcome the newly discovered taxane resistance mechanism. “Starting with a database of approved drugs, we created a computational program that was able to screen through these molecules, in silico, to identify the ones that would essentially make resistant cells look more like cells that are sensitive to taxanes,” said co-senior author Dr. Olivier Elemento, director of the Caryl and Israel Englander Institute for Precision Medicine, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and a professor of physiology and biophysics at Weill Cornell Medicine.
A surprising candidate was identified by the algorithm: imatinib, a leukemia drug sold under the brand name Gleevec. Imatinib’s known mechanism of action is unrelated to that of taxanes, and it has no clinical indications for gastric cancer. Nonetheless, the researchers confirmed in lab dishes that a combination of the two drugs kills taxane-resistant tumors.
Dr. Elemento, who is also a co-founder and equity stakeholder of OneThree Biotech, an artificial intelligence-driven drug discovery and development company, said, “That’s important because it demonstrates how you can go in without preconceptions and use computational screening to come up with molecules that have an effect.”
Because imatinib is already on the market, the researchers hope to begin clinical trials on the combined treatment as soon as possible. Variants of CLIP-170 could be used as biomarkers for taxane resistance in a variety of solid tumors. “The entire story is truly remarkable,” Dr. Shah said, “and it opens the door for overcoming taxane resistance in other cancers as well.”
