Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F

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In an article recently published in the New England Journal of Medicine, Alice Shaw MD PhD and her colleagues presented a case of a patient with metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer who developed resistance to therapy with crizotinib.
Relapse and resistance after treatment with first generation ALK inhibitors, like crizotinib, is not uncommon. In this particular case the mutation responsible for crizotinib resistance was a substitution of one amino acid (C1156Y). The patient subsequently underwent treatment with a lorlatinib, a third generation inhibitor being developed by Pfizer, responded transiently and eventually relapsed again. The tumor was biopsied after the second relapse and revealed a new mutation (L1198F) which conferred resistance to lorlatinib as well as the previous C1156Y mutation.
Paradoxically, this newly acquired second mutation, in the ALK gene, reversed acquired resistance to crizotinib by altering the structure of the protein and re-exposing the binding site. The patient was retreated with crizotinib and responded well.
This article illustrates the complex interplay that can occur between multiple somatic mutations occurring on the same protein. In this case it was to the benefit of the patient as it reinstated sensitivity to the drug. This case also exemplifies the importance of multiple generations of drugs for one therapeutic target. Furthermore, functional characterization of mutations was paramount in this case and with this information the physician was able to make the unconventional decision to reuse a drug to which resistance already developed.