{"entity":{"id":"paper-shaw-alk-l1198f-resensitisation-nejm-2016","kind":"paper","name":"Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-25","links":[{"label":"Shaw et al., N Engl J Med 2016: resensitisation to crizotinib by the lorlatinib resistance mutation ALK L1198F","url":"https://doi.org/10.1056/NEJMoa1508887"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26698910/"}],"tags":[],"related":["alk-fusion"],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors","cgp"],"targets":["alk"],"drugs":["crizotinib","lorlatinib"],"companies":[],"institutions":["mgh"],"pathways":["resistance-routes-map","rtk-activation","clonal-evolution"],"terms":["resistance","cross-resistance"],"trials":[],"people":["alice-shaw"],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/NEJMoa1508887","pmid":"26698910","authors":"Shaw AT, Friboulet L, Leshchiner I, et al.","paperType":"translational","findings":["A compound ALK mutation, C1156Y with L1198F, conferred resistance to lorlatinib.","The same compound mutation restored crizotinib binding.","Rechallenge with crizotinib produced clinical recovery."],"whatItMeans":"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.","caveats":["A single patient.","Compound mutations of this kind are rare.","The strategy has not been tested prospectively."],"changedPractice":false,"participants":1},"route":"/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/","neighbours":{"biomarker":[{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","route":"/biomarkers/alk-fusion/"},{"id":"alk-resistance-mutation","kind":"biomarker","name":"ALK kinase-domain resistance mutation (G1202R and the rest)","route":"/biomarkers/alk-resistance-mutation/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"}],"drug":[{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"}],"institution":[{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"cross-resistance","kind":"term","name":"Cross-resistance","route":"/terms/cross-resistance/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"person":[{"id":"alice-shaw","kind":"person","name":"Alice T. Shaw","route":"/people/alice-shaw/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}]}}