A Cancer One-Two Punch

Lung cancer treatment resistance to ALK inhibitors may restore sensitivity to targeted drugs

(RxWiki News) Teaching an old drug a new trick may not be so far-fetched.

Drugs designed to target the genetic mutations driving cancer growth have revolutionized cancer treatment. But in almost every case, the cancer eventually becomes resistant to these drugs and begins to grow again. To combat this resistance, patients are often switched to more powerful drugs.

In a new report, researchers from Massachusetts General Hospital (MGH) detailed the pattern of drug resistance in one lung cancer patient who was treated with multiple targeted therapies. When this patient developed resistance to her third targeted therapy, researchers found that her cancer’s sensitivity to the very first therapy used was restored. That drug was a first-generation ALK inhibitor called crizotinib (brand name Xalkori).

"For patients relapsing on first-generation inhibitors like crizotinib, treatment with more potent and selective next-generation inhibitors can be very effective," said lead study author Alice Shaw, MD, PhD, of MGH Cancer Center, in a press release. "However, cancers that become resistant to next-generation inhibitors are usually also resistant to less potent first-generation inhibitors. It caught us by surprise to discover a mutation that could cause both resistance to a newer next-generation inhibitor and re-sensitization to the older, first-generation inhibitor."

In this report, Dr. Shaw and team looked at one woman, age 52, with metastatic non-small cell lung cancer. She was first treated with crizotinib, then with a second first-generation ALK inhibitor called ceritinib (Zykadia), followed by a third-generation inhibitor called lorlatinib.

Over the course of her disease, a number of biopsies were performed to better understand why treatment resistance had developed.

After crizotinib failed, Dr. Shaw and team identified a mutation that also made her resistant to ceritinib. Although lorlatinib was able to suppress this mutation, a second mutation eventually emerged. After nine months, lorlatinib stopped working and her cancer started growing again — leaving her on the brink of liver failure and death.

She was then switched back to crizotinib where, within a few weeks, her liver function returned to normal. This change was atributed to the new lorlatinib-resistant mutation restoring the cancer's response to crizotinib.This response lasted for six months.

"These results highlight how important it is to obtain repeat biopsies in patients who relapse on targeted therapies," Dr. Shaw said. "In some cases, this information can then help us to select the next therapy that's most likely to be effective."

This study was published Dec. 24 in The New England Journal of Medicine.

Pfizer, the National Cancer Institute and the National Foundation for Cancer Research funded this research. No conflicts of interest were disclosed.

Review Date: 
December 27, 2015