Screening Strategy May Help Overcome Resistance

A new screening platform that uses cells grown from patients' own tumor biopsies may offer a way to rapidly identify drug combinations capable of overcoming resistance to treatment, a new study reports.

With the aid of recently developed technology, researchers created cell culture models from biopsy samples from patients with non–small cell lung cancer whose tumors had resisted treatment with EGFR or ALK tyrosine kinase inhibitors (TKI). After analyzing the cells for genetic mutations and performing a pharmacological screen, they identified drug combinations that might be effective, some of which would not have been predicted by genetic analysis alone. The results were published online in Science.

“For some cases of resistance, genetic analysis clearly points to effective therapies,” says Jeffrey Engelman, MD, PhD, director of thoracic oncology and molecular therapeutics at Massachusetts General Hospital Cancer Center in Boston, MA, and co–senior author of the study. “But in cases where the genetic analysis is ambiguous, the functional screen is effective in identifying therapeutic combinations.”

Engelman's team proved the effectiveness of the new strategy by screening five cell lines previously developed in vitro against a panel of 76 targeted drugs, both alone and in combination with first-line therapies to which the tumors no longer responded. The process accurately identified drugs that target known resistance bypass tracks, or alternate signaling pathways developed by resistant cells, in all of the models.

The screening was then applied to 55 models of acquired resistance with unknown mechanisms of resistance, 35 derived in vitro and 20 from patient biopsies. The strategy identified at least one effective drug combination for 45 out of the 55 cell lines, several of which would not have been detected by genetic analysis alone.

For example, a previously uncharacterized FGFR3 variant was identified as a key contributor to resistance in one patient-derived cell line with acquired resistance to EGFR TKIs. Subsequent follow-up studies showed that FGFR inhibitors resensitized these cells to EGFR inhibitors, allowing for a potentially actionable therapeutic strategy in that patient.

The study also revealed that inhibiting ALK led to activation of SRC-controlled pathways that promote resistance, and about half of the ALK-positive tumors could be resensitized by an SRC inhibitor.

“We found that activation of SRC is how the cancer cells adapted to inhibition of ALK,” Engelman says. In mouse studies, the ALK–SRC inhibitor combination was effective in delaying the emergence of resistance in multiple models.

The investigators are now assessing the screening platform on drug-resistant colorectal and breast tumor samples and may test other cancer types in the future, Engelman says.

“We'd like to be able to produce this data in a timeframe that could be used by patients and physicians to guide treatment,” he says. “Our goal is to develop this assay so that we could potentially biopsy a patient and get the results of the screens back within 3 to 4 weeks to help with patient decisions.”