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A patient's cancer became resistant to one drug, then to a second, then to a third, and the mutation that defeated the third drug made the first one work again. She was rechallenged with it and recovered.
In a patient with metastatic ALK-rearranged lung cancer, resistance to crizotinib developed through a C1156Y mutation in the ALK kinase domain. Her tumour did not respond to a second-generation ALK inhibitor but did respond to lorlatinib. When her tumour relapsed, sequencing revealed an ALK L1198F mutation in addition to C1156Y. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding, but paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitising the cancer to crizotinib. The patient received crizotinib again and her cancer-related symptoms and liver failure resolved.
It is the cleanest demonstration in oncology that resistance is a property of a particular drug bound to a particular protein rather than a property of the tumour, and that genotyping at every progression can reopen an option that looked closed.
Shares Alice T. Shaw, ALK kinase-domain resistance mutation (G1202R and the rest), ALK fusion (ALK-positive), Lorlatinib.
Shares Cross-resistance, ALK kinase-domain resistance mutation (G1202R and the rest), ALK fusion (ALK-positive), Lorlatinib.
Shares Alice T. Shaw, Massachusetts General Hospital Cancer Center, Crizotinib, ALK.
Shares Alice T. Shaw, Lorlatinib, Crizotinib, ALK.
Shares ALK fusion (ALK-positive), Crizotinib, ALK, Receptor tyrosine kinase activation.
Shares Alice T. Shaw, Crizotinib, New England Journal of Medicine.
Shares Alice T. Shaw, Massachusetts General Hospital Cancer Center, Crizotinib, ALK.
Shares Massachusetts General Hospital Cancer Center, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation.