Drug Resistance

COSMIC has started to annotate mutations identified in the literature as resistance mutations, including those conferring acquired resistance (after treatment) and intrinsic resistance (before treatment). This is a work in progress which we aim to expand, including the curation of 2 or more drug treatments and responses.

Resistance to targeted drug treatment occurs in some patients following an initial drug response. This can be caused by the development of resistance mutations, such as those in the drug target preventing drug binding. Acquired resistance develops gradually within the tumour where subpopulations of cells may acquire or already have the mutations enabling them to emerge under selective drug pressure. Patients who initially responded to treatment relapse as a result of the emergence of the dominant resistant clone. Screening patients for mutations at tumour recurrence identifies these new mutations which were not present (at detectable levels) in the primary pre-treatment tumour. Functional studies may confirm the role of these secondary mutations in resistance.

Alternative transcripts are also displayed here for genes where reported resistant mutations are not located on the canonical transcript but are on the alternative, and also where reported resistant mutations are located at the same genomic position on both the canonical and alternative transcripts or on overlapping genes and/or fusions and share a COSM id.

Table to view drug and gene mutation frequency

Drug	Genes	Unique Resistant Samples	Unique Resistant Mutations
Imatinib	ABL1, ABL1_ENST00000318560, KIT, PDGFRA	1370	189
Tyrosine kinase inhibitor - NS	ABL1, , ABL1_ENST00000318560, EGFR, EGFR_ENST00000454757 (GRCH38),EGFR_ENST00000455089, EGFR_ENST00000442591 (GRCH37)	386	71
Gefitinib	EGFR, EGFR_ENST00000454757 (GRCH38), EGFR_ENST00000442591 (GRCH37), EGFR_ENST00000455089	238	9
Erlotinib	EGFR, EGFR_ENST00000454757 (GRCH38), EGFR_ENST00000442591 (GRCH37)	84	5
Crizotinib	ALK, ALK_ENST00000431873 (GRCh37), ALK_ENST00000618119 (GRCh38), MET, MET_ENST00000397752, MET_ENST00000539704	73	50
Endocrine therapy	ESR1, ESR1_ENST00000206249, ESR1_ENST00000338799, ESR1_ENST00000406599, ESR1_ENST00000427531, ESR1_ENST00000443427, ESR1_ENST00000456483	71	54
Dasatinib	ABL1, ABL1_ENST00000318560	66	11
Purine Analogue	NT5C2, NT5C2_ENST00000404739, NT5C2_ENST00000423468, NT5C2_ENST00000470299	57	81
Ibrutinib	BTK, BTK_ENST00000372880 (GRCh37), BTK_ENST00000308731(GRCh38)	51	18
Afatinib	EGFR, EGFR_ENST00000454757 (GRCH38), EGFR_ENST00000442591 (GRCH37), EGFR_ENST00000455089	48	6
Osimertinib	EGFR, EGFR_ENST00000454757 (GRCH38), EGFR_ENST00000442591 (GRCH37), EGFR_ENST00000455089	48	62
Vismodegib	SMO	42	19
Vemurafenib	BRAF, BRAF_ENST00000288602 (GRCh38)	24	7
Ceritinib	ALK, ALK_ENST00000431873 (GRCh37), ALK_ENST00000618119 (GRCh38)	23	11
Alectinib	ALK, ALK_ENST00000431873 (GRCh37), ALK_ENST00000618119 (GRCh38)	18	14
Dabrafenib	BRAF, BRAF_ENST00000288602(GRCh38)	15	4
Quizartinib	FLT3, FLT3_ENST00000380982 (GRCh37), FLT3_ENST00000537084	13	14
Nilotinib	ABL1, ABL1_ENST00000318560, KIT	13	11
Lorlatinib	ALK, ALK_ENST00000431873 (GRCh37), ALK_ENST00000618119 (GRCh38)	11	11
Sorafenib	FLT3, FLT3_ENST00000380982 (GRCh37), FLT3_ENST00000537084	11	11
BGJ398	FGFR2,FGFR2_ENST00000346997,FGFR2_ENST00000351936,FGFR2_ENST00000356226,FGFR2_ENST00000357555,FGFR2_ENST00000358487, FGFR2_ENST00000360144, FGFR2_ENST00000369056, FGFR2_ENST00000369059, FGFR2_ENST00000369060, FGFR2_ENST00000369061, FGFR2_ENST00000478859	9	29
Pemigatinib	FGFR2_ENST00000358487	8	6
Bosutinib	ABL1, ABL1_ENST00000318560	7	7
Brigatinib	ALK	6	4
Sunitinib	KIT, PDGFRA, FLT3, FLT3_ENST00000380982 (GRCh37) , FLT3_ENST00000537084	6	7
PD0325901	MAP2K1, MAP2K2	3	3
Pembrolizumab	JAK1, JAK2, JAK2_ENST00000539801 (GRCh37)	3	4
Capmatinib	MET, MET_ENST00000397752, MET_ENST00000539704	2	6
Selumetinib	MAP2K1	1	1
PF-04217903	MET, MET_ENST00000397752	1	1
Savolitinib	MET, MET_ENST00000397752	1	3
Ivosidenib	IDH1, IDH1_ENST00000345146,IDH1_ENST00000446179	14	9
Enasidenib	IDH2, IDH2_ENST00000539790(GRCh37),IDH2_ENST00000540499,IDH2_ENST00000559482	2	6

Other patients are refractory to drug therapy and have intrinsic, or primary, drug resistance. They show no initial response to a drug treatment because the tumour may have pre-existing resistance mutations.

Tumours which have received drug therapy and have a reported drug response are annotated in COSMIC using a Drug Response Tumour Feature based on RECIST (Response Evaluation Criteria in Solid Tumours) criteria:

RECIST	COSMIC
complete response (CR)	clinical complete response
partial response (PR)	clinical partial response
stable disease (SD)*	clinical primary non response
progressive disease (PD)	clinical primary non response

In addition, COSMIC uses the following annotations for Drug Responses:

-- clinical resistant recurrence (for recurrent tumours displaying drug resistance)
-- clinical response - not further specified (i.e. unclear if partial or complete response or where an author has considered stable disease a response*)
-- clinical non-response - not further specified (i.e. unclear if primary or acquired (secondary) resistance)
-- in vitro resistant (for cell line studies)
-- in vitro sensitive (for cell line studies)
-- xenograft response (used for partial response, complete response)
-- xenograft non response

* Stable disease may be annotated as a “clinical response – not further specified” where stable disease is considered by an author as a positive response to therapy and/or where stable disease has been followed by a relapse.

Acquired resistance mutations will occur in tumours annotated as a resistant recurrence e.g. Imatinib clinical resistant recurrence. A recurrent tumour or a metastatic site has been screened for mutations following relapse after an initial drug response. Only those secondary mutations reported as proven to be associated with resistance or presumed by authors to be associated with resistance, e.g. based on their gene location, are annotated as acquired resistance mutations and not incidental passenger mutations detected in a recurrent tumour.

Intrinsic resistance mutations will occur in tumours annotated as having a primary non response e.g. Imatinib clinical primary non response. Only those mutations reported as associated with resistance are annotated as primary resistance mutations.

Where there is a resistance mutation reported in a tumour but it is not possible to identify it as an intrinsic or acquired mutation the following annotation is used e.g. Imatinib clinical non response - not further specified.

Differing drug doses can affect whether a tumour responds to therapy or not, and therefore our drug response annotations will include noise as a result of the different treatment regimens used on individual patients.

COSMIC v101 includes data for following drugs: Vismodegib, Vemurafenib, Osimertinib, Ceritinib, Erlotinib, Gefitinib, Imatinib, Ibrutinib, Nilotinib, Tyrosine kinase inhibitor - NS, Afatinib, Endocrine therapy, Alectinib, PD0325901, Dasatinib, Crizotinib, Selumetinib, Sunitinib, Dabrafenib, Bosutinib, Brigatinib,Quizartinib, Savolitinib, Capmatinib, PF-04217903, Lorlatinib, Pembrolizumab, Purine Analogue, BGJ398, Pemigatinib and Sorafenib

Follow the links below to the 15 genes with drug resistance data -

ABL1 ALK BRAF BTK EGFR ESR1 FLT3 KIT MAP2K1 MAP2K2 PDGFRA SMO MET JAK1 JAK2