GRCh38 · COSMIC v92


This section shows a general overview of information for the selected study (COSU identifier) or publication (COSP identifier). Studies may have been performed by the Sanger Institute Cancer Genome Project, or imported from the ICGC/TCGA. You can see more information on the help pages.

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer.
Paper ID
Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, Dardaei L, Prutisto-Chang K, Dagogo-Jack I, Timofeevski S, Hubbeling H, Gainor JF, Ferris LA, Riley AK, Kattermann KE, Timonina D, Heist RS, Iafrate AJ, Benes CH, Lennerz JK, Mino-Kenudson M, Engelman JA, Johnson TW, Hata AN and Shaw AT
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
Cancer discovery, 2018;8(6):714-729
ISSN: 2159-8290
PMID: 29650534 (view at PubMed or Europe PMC)
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of <i>ALK</i> mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, <i>N</i>-ethyl-<i>N</i>-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single <i>ALK</i> mutations. In similar screens with EML4-ALK containing single <i>ALK</i> resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound <i>ALK</i> mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound <i>ALK</i> mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of <i>ALK</i> mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound <i>ALK</i> mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.<b>Significance:</b> Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound <i>ALK</i> mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. <i>Cancer Discov; 8(6); 714-29. ©2018 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 663</i>.
Paper Status
Genes Analysed
Mutated Samples
Total No. of Samples

Mutation Matrix

This section shows the correlation plot between the top 20 genes and samples. There is more information in our help pages.


This table shows genes with mutations in the selected study/paper [more details]
Genes Mutated Samples
This table shows genes without mutations in the selected study/paper [more details]
Non-Mutant Genes Gene Id (COSG)


This tab shows genes with mutations in the selected study/paper [more details]

Genes Samples CDS Mutation AA Mutation

This tab shows non coding variant in the selected study/paper [more details]

Sample ID Sample Name ID NCV Annotation Zygosity Chromosome Genome start Genome stop Genome version Strand WT seq Mut seq FATHMM-MKL

This tab shows the gene expression and copy number variation data for this study [more details]

Table Information


The table currently shows all copy number data. This includes non-numeric data with descriptive definitions of gain/loss.

To Include only high value (numeric) copy number data, please click here. For more detailed information about copy number data and gain/loss definitions click here.

Sample Gene Expression Expr Level (Z-Score)

Over Expressed; Z-Score > 2.0

Under Expressed; Z-Score < -2.0

Normal; Z-Score within the range -2.0 to 2.0

CN Type Minor Allele Copy Number CN Segment Posn. Average Ploidy

1. N/A represents cases where the average ploidy value is not available( mostly ICGC samples). For some TCGA samples where the minor allele information is not available the average ploidy value could not be calculated.

2. For TCGA samples, the ASCAT algorithm was used to calculate the average ploidy.

3. For CGP samples, the PICNIC algorithm was used to calculate the average ploidy.


This table lists the samples in the selected study which have low/high methylation for each gene. [more details]

No data

This tab shows the fusion mutations observed in this sample [more details]

Gene Sample Name Id Sample(COSS) CDS Mutation Somatic status Zygosity Validated Type


This table shows mutated samples in the selected study/paper.

Sample Name Mutation Count

This table shows samples without mutations in the selected study/paper.

Non-Mutant Samples Sample Id (COSS)