Combating Patients' Resistance to Targeted Cancer Drugs

Drugs targeting genetic mutations that drive tumor growth have revolutionized treatment for some serious forms of cancer, but the tumors usually become resistant to the drugs’ therapeutic effects and resume growth, often through the development of new mutations.

A case study published in The New England Journal of Medicine describes the evolution of drug resistance in a patient with metastatic non-small-cell lung cancer driven by a mutation involving the ALK gene. The patient was treated with multiple different targeted therapies and the report describes how she developed resistance to the third targeted therapy, and how the new mutation actually restored her response to the first targeted therapy drug used.

The 51-year-old patient was first treated with crizotinib, then with a second ALK inhibitor, ceritinib, and finally by the newest-generation ALK inhibitor, lorlatinib. The final treatment led to a reduction in the patient’s tumor burden for 9 months, but then her liver metastases resumed growing and she was at the brink of liver failure and death. She was again put on crizotinib, and within a few weeks had dramatically improved, with liver function returning to normal. The patient’s response to crizotinib lasted approximately 6 months.

Lead author Alice Shaw, MD, PhD, of Massachusetts General Hospital, said that the case caught the team by surprise.

“For patients relapsing on first-generation inhibitors like crizotinib, treatment with more potent and selective next-generation inhibitors can be very effective,” she noted. “However, cancers that become resistant to next-generation inhibitors are usually also resistant to less potent first-generation inhibitors.”

The discovery of a mutation that could cause both resistance to a newer-generation inhibitor and resensitization to the older, first-generation inhibitor caused dramatic improvement in the patient’s condition.

A number of biopsies were performed over the course of the disease to study why resistance developed. The physicians identified the first resistance mutation after the patient relapsed on crizotinib, which also made her resistant to ceritinib. Lorlatinib was able to suppress this mutation, but a second mutation eventually developed. That mutation provided a high level of resistance to lorlatinib and other next-generation ALK inhibitors, they found, but it also restored sensitivity to crizotinib and made the patient’s cancer even more responsive to crizotinib, which is a less potent and selective ALK inhibitor.

“These results highlight how important it is to obtain repeat biopsies in patients who relapse on targeted therapies,” Dr Shaw noted.

Molecular profiling of biopsies can uncover novel mechanisms of resistance that in some cases can help physicians to select the therapies that are most likely to be effective.