Drugs that inhibit enzymes called tyrosine kinases are among the most effective targeted cancer treatments. Yet, they only benefit about 40 to 80 percent of the patients expected to respond.
MIT researchers found that many tumors keep growing by activating an alternative survival pathway, even when drugs block the main pathway.
“The cells seem to carry this mechanism themselves, activating a crucial survival pathway in cancer,” says Forest White, the Ned C. and Janet C. Rice Professor of Biological Engineering at MIT. “It enables the cells to resist a wide range of treatments, including chemotherapy.
The researchers also discovered that combining a tyrosine kinase inhibitor with a drug that blocks the backup survival pathway can effectively kill drug-resistant cancer cells. Clinical trials are currently testing one such combination in lung cancer patients.
Forest White is the senior author of the study, published this week in the Proceedings of the National Academy of Sciences. The lead author is Cameron Flower, PhD ’24, now a postdoctoral researcher at Dana-Farber Cancer Institute and Boston Children’s Hospital.
Cancer Cell Survival
Tyrosine kinases play a key role in cellular signaling, helping cells detect external signals and respond by processes like growth or division. Human cells contain around 90 different tyrosine kinases, many of which are overactive in cancer cells.
“These kinases are crucial for controlling cell growth and mitosis,” says Cameron Flower. “Transitioning a cell from a nondividing state to division relies on the activity of multiple tyrosine kinases. In cancer cells, we often see these kinases mutated or overproduced.”
Cancer-related kinases include EGFR and BCR-ABL. Several drugs, such as imatinib (Gleevec), target these kinases and are approved for treating leukemia and other cancers. Yet, these treatments don’t work for all patients whose tumors overexpress tyrosine kinases — a puzzling issue for researchers.
This inconsistent effectiveness prompted the MIT team to investigate why some tumors fail to respond to these therapies.
For the study, the researchers analyzed six cancer cell lines derived from lung cancer patients. They selected two lines with EGFR mutations, two with mutations in the tyrosine kinase MET, and two with mutations in ALK. Within each pair, one line responded well to a tyrosine kinase inhibitor targeting the overactive pathway, while the other did not.
Using phosphoproteomics, the team examined the signaling pathways active in each cell before and after treatment. “This technique identifies proteins that kinases have phosphorylated, as these enzymes add phosphate groups to proteins, activating or deactivating them.”
A Hidden Survival Network Enables Resistance
The analysis showed that the drugs successfully blocked their intended kinase targets in all cells. However, in the resistant cells, a separate signaling network was already active, allowing the cells to survive despite the treatment.
“Even before treatment starts, the cells are inherently resistant to the drug,” says Cameron Flower.
This survival network is driven by signaling pathways controlled by SRC family kinases. Activating this network appears to help cancer cells grow and potentially spread to other parts of the body. Beyond lung cancer, White’s lab has also observed SRC kinases active in melanoma, where they contribute to drug resistance, and in glioblastoma, a type of brain cancer.
Benjamin Neel, a medicine professor at NYU Grossman School of Medicine who was not involved in the study, notes that targeting SRC kinases with drugs could expand patient benefit by combining SRC inhibitors with driver-oncogene inhibitors. This approach deserves testing in clinical trials.”
The findings may also explain why some patients who initially respond to tyrosine kinase inhibitors later experience tumor recurrence: the cancer cells may activate this same survival pathway sometime after the initial treatment.
Overcoming Drug Resistance
The researchers discovered that combining a tyrosine kinase inhibitor with an SRC family kinase inhibitor significantly increased cell death in resistant cancer cells. Coincidentally, a clinical trial testing this combination—using the tyrosine kinase inhibitor osimertinib alongside an SRC inhibitor—is already underway in lung cancer patients. The MIT team hopes to collaborate with the same drug company to conduct a similar trial in pancreatic cancer.
They also showed that researchers can use phosphoproteomics on patient biopsy samples to identify cells where SRC pathways are already active.
“We’re very excited to follow these clinical trials and see how patients respond to these combinations. I believe tyrosine phosphoproteomics could play an important role in guiding clinical decisions in the future,” says Forest White.
This approach could also help patients whose tumors initially respond to tyrosine kinase inhibitors but later develop resistance by activating SRC pathways.
“Some of the sensitive cells can switch on this survival pathway and persist, potentially forming the residual disease that remains after treatment,” says Forest White. “An exciting question is whether we can enhance therapy for nearly all patients, whether their tumors show inherent or adaptive resistance.”
The National Institutes of Health and the MIT Center for Precision Cancer Medicine supported the study.
Read the original article on: MIT News
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