Drug Resistance Became Tumor Resensitization in a Unique Case of a Patient With Lung Cancer

Drug Resistance Became Tumor Resensitization in a Unique Case of a Patient With Lung Cancer
Drug Resistance Became Tumor Resensitization in a Unique Case of a Patient With Lung Cancer

The evolution of drug resistance in a patient with lung cancer was demonstrated in a case published in the New England Journal of Medicine (doi:10.1056/NEJMoa1508887). Molecular analysis of a liver metastasis lesion revealed resistance to a third targeted therapy; however, the new mutation restored tumor response to the first targeted therapy used to treat this patient.

Drugs that target the genetic mutations driving the growth of tumors have revolutionized the treatment of several cancers. But in almost every case, tumors become resistant to the drugs' therapeutic effects and resume growth, often through the emergence of new mutations, in turn spurring the development of more powerful drugs to overcome the resistance mutations.

Treatment with more potent and selective next-generation inhibitors can be very effective in patients who relapse after treatment with first-generation inhibitors such as crizotinib, reported Alice Shaw, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center in Boston, and colleagues.

"However, cancers that become resistant to next-generation inhibitors are usually also resistant to less potent first-generation inhibitors,” Shaw explained. “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."

The patient was a 52-year-old woman with metastatic non-small cell lung cancer driven by a chromosomal rearrangement involving the ALK gene. She was first treated with crizotinib; then with a second ALK inhibitor, ceritinib; followed by the newest next-generation ALK inhibitor, lorlatinib.

Preclinical studies showed lorlatinib to be effective against all known resistance mutations in the ALK gene. In this patient, the drug reduced the tumor burden for 9 months. Then her liver metastases resumed growing, bringing her to the brink of liver failure and death. Based on molecular analysis of the mutations in a resistant liver lesion, the patient was switched back to crizotinib. Within a few weeks, she experienced a dramatic improvement and her liver function returned to normal. Tumor response to crizotinib lasted for approximately 6 months.

Over the course of her disease, the patient underwent several biopsies to understand why resistance had developed. After she relapsed on crizotinib, the first resistance mutation was identified, also rendering her resistant to ceritinib. Although lorlatinib suppressed this mutation, a second resistance mutation emerged. That mutation conferred high-level resistance to lorlatinib and other next-generation ALK inhibitors; however, it unexpectedly restored tumor sensitivity to crizotinib. In fact, the tumor was even more responsive to crizotinib, a less potent and less selective inhibitor of ALK.

"These results highlight how important it is to obtain repeat biopsies in patients who relapse on targeted therapies," said Shaw, who is also an associate professor of Medicine at Harvard Medical School. "Molecular profiling of these biopsies can uncover novel mechanisms of resistance. In some cases, this information can then help us to select the next therapy that's most likely to be effective."

Multiple structurally distinct inhibitors have been developed to treat ALK-positive lung cancer, and all of them target the same ALK oncogene. Often these drugs can be used in sequence, one after the other. This case suggests that the sequence of ALK inhibitors used may best be determined by the underlying resistance mechanism. It also introduces the possibility that combining ALK inhibitors may block the development of resistance mutations and extend remission duration. Clinical studies that examine the effects of different combinations of targeted therapies are needed, Shaw added.

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