Perhaps the biggest challenge in precision cancer therapy is tumors’ nasty habit of rebounding after an initial attack with targeted drugs has shrunk them almost out of existence. Instead of vanishing completely, curing the patient, the tumors leave behind a small cadre of cells that slumber in a dormant state, only to return in a dangerous, drug-resistant form.
Despite the high hopes and initial success of cancer therapy using “smart” drugs that target genetic changes in cancer cells, such treatment “rarely, if ever, leads to complete tumor eradication,” say Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology, and co-authors of a report in the journal CANCER CELL. “The residual tumors, following treatment, can serve as reservoirs for the development of acquired drug resistance.”
For example, patients with advanced non-small cell lung cancer whose tumor cells have a mutant EGFR gene typically have a dramatic response to inhibitor drugs that target those cells. But sooner or later, after a period of inactivity, the cancer almost always recurs, having acquired new skills for survival and growth.
In their published report, Jänne and his colleagues say they have discovered a mechanism within lung cancer cells that enables the cells to lie dormant and avoid destruction by the cancer drugs. The investigators say their research suggests a strategy for reducing the number of residual cancer cells and improving patient outcomes.
The scientists, including first author Kari J. Kurppa, PhD, carried out their experiments with EGFR mutant non-small cell lung cancer cells as a model of the more general tendency of many cancers to rebound following treatment with targeted drugs called tyrosine kinase inhibitors. In these experiments, the cancer cells were exposed to a drug that inhibits the mutant EGFR protein and another drug that targets the MEK protein.
They discovered that a pair of regulatory proteins called YAP and TEAD can become over-activated in cancer cells in response to treatment with targeted inhibitor drugs. In addition, they report that high YAP/TEAD activity in combination with a third protein, SLUG, suppresses a key cell-death or pro-apoptosis protein, BMF, that normally would cause the cancer cells to self-destruct when exposed to the cancer drug. Along with these changes, the cancer cells enter a dormant state, retaining the capability of re-establishing the tumor at a later time.
With this information in hand, the researchers partnered with Nathanael Gray, PhD, and his chemical biology team who developed a new compound that inhibits the TEAD protein. When the TEAD inhibitor was tested in combination with an EGFR inhibitor on lung cancer cells, cell death was increased.
These results, the investigators say, suggest that adding TEAD inhibitors to targeted drug treatment of cancers might hamper the cancer cells’ ability to become dormant and return in a resistant state. These inhibitors will need to be developed further and ultimately tested in a clinical trial, they note. If successful, the combination of standard targeted drugs and agents that block cancer cells’ tendency to hide in a dormant state could lead to better outcomes for patients.