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.
Table to view drug and gene mutation frequency
| Drug | Genes | Unique Resistant Samples | Unique Resistant Mutations |
|---|---|---|---|
| Imatinib | ABL1, KIT, PDGFRA | 1146 | 156 |
| Tyrosine kinase inhibitor - NS | ABL1, EGFR | 353 | 59 |
| Gefitinib | EGFR | 195 | 3 |
| Erlotinib | EGFR | 70 | 2 |
| Endocrine therapy | ESR1 | 60 | 10 |
| Vismodegib | SMO | 41 | 18 |
| Dasatinib | ABL1 | 40 | 9 |
| Afatinib | EGFR | 28 | 2 |
| Crizotinib | ALK, MET | 22 | 16 |
| Nilotinib | ABL1, KIT | 13 | 10 |
| Quizartinib | FLT3 | 11 | 5 |
| Vemurafenib | BRAF | 10 | 5 |
| Sorafenib | FLT3 | 10 | 4 |
| Ceritinib | ALK | 8 | 6 |
| Alectinib | ALK | 8 | 5 |
| Dabrafenib | BRAF | 8 | 3 |
| Osimertinib | EGFR | 7 | 2 |
| Bosutinib | ABL1 | 7 | 5 |
| Sunitinib | KIT, PDGFRA, FLT3 | 5 | 4 |
| PD0325901 | MAP2K1, MAP2K2 | 3 | 3 |
| Selumetinib | MAP2K1 | 1 | 1 |
| Savolitinib | MET | 1 | 1 |
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 v81 includes data for following drugs: Vismodegib, Vemurafenib, Osimertinib, Ceritinib, Erlotinib, Gefitinib, Imatinib, Nilotinib, Tyrosine kinase inhibitor - NS, Afatinib, Endocrine therapy, Alectinib, PD0325901, Dasatinib, Crizotinib, Selumetinib, Sunitinib, Dabrafenib, Bosutinib, Quizartinib and Sorafenib
Follow the links below to the 12 genes with drug resistance data -
ABL1 ALK BRAF EGFR ESR1 FLT3 KIT MAP2K1 MAP2K2 PDGFRA SMO MET