# Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer

Source: https://onco.cc/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/  
OnCo record `paper-gainor-alk-resistance-mutations-cancer-discov-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Rebiopsying 103 patients as each generation of drug failed showed that each drug leaves its own signature of escape mutations, and that whether a mutation is present decides whether the next drug in the sequence will work.

## Summary

One hundred and three repeat biopsies from patients with ALK-positive lung cancer progressing on various ALK inhibitors were analysed. Each ALK inhibitor was associated with a distinct spectrum of ALK resistance mutations, and the frequency of ALK G1202R increased significantly after treatment with second-generation agents. Second-generation inhibitors are generally effective after crizotinib even without a crizotinib-resistant ALK mutation, reflecting incomplete inhibition of ALK by crizotinib in many cases. In a series of ceritinib-resistant patient-derived cell lines, the presence of ALK resistance mutations was highly predictive of sensitivity to the third-generation inhibitor lorlatinib, whereas lines without ALK mutations were resistant.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Cancer Discovery
- Year: 2016
- DOI: 10.1158/2159-8290.CD-16-0596
- Authors: Gainor JF, Dardaei L, Yoda S, et al.
- Findings: Each ALK inhibitor generation leaves a distinct spectrum of resistance mutations.; G1202R rises significantly in frequency after second-generation treatment.; Second-generation drugs work after crizotinib whether or not a resistance mutation is present.; Lorlatinib sensitivity in cell lines tracks the presence of an ALK mutation.
- What it means: It made repeat biopsy and genotyping at progression the standard in ALK-positive lung cancer, because after a second-generation inhibitor the presence or absence of an ALK mutation is what separates patients who should receive a third-generation inhibitor from those who should not.
- Caveats: Biopsies come from patients whose disease could be sampled, which selects for accessible lesions.; Cell line predictions were later confirmed in patients but with weaker separation.; Resistance that is ALK-independent was not characterised in detail.

## Sources

- Gainor et al., Cancer Discov 2016: 103 repeat biopsies and the resistance mutations of first- and second-generation ALK inhibitors: https://doi.org/10.1158/2159-8290.CD-16-0596
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27432227/

## Connected records

- biomarkers: [ALK fusion (ALK-positive)](https://onco.cc/biomarkers/alk-fusion/), [ALK kinase-domain resistance mutation (G1202R and the rest)](https://onco.cc/biomarkers/alk-resistance-mutation/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Patient-derived organoids](https://onco.cc/technologies/organoids/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [ALK](https://onco.cc/targets/alk/)
- drugs: [Alectinib](https://onco.cc/drugs/alectinib/), [Brigatinib](https://onco.cc/drugs/brigatinib/), [Ceritinib](https://onco.cc/drugs/ceritinib/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/)
- institutions: [Massachusetts General Hospital Cancer Center](https://onco.cc/institutions/mgh/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Biopsy](https://onco.cc/terms/biopsy/), [Cross-resistance](https://onco.cc/terms/cross-resistance/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene fusion](https://onco.cc/terms/gene-fusion/)
- people: [Justin F. Gainor](https://onco.cc/people/justin-gainor/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)

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