The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells.
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting "undruggable" proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.
Pubmed ID: 39755121 RIS Download
Research resources used in this publication
- Huh-7 (RRID:CVCL_0336) (cell line)
- HAP1 (RRID:CVCL_Y019) (cell line)
- MDA-MB-468 (RRID:CVCL_0419) (cell line)
- LS180 (RRID:CVCL_0397) (cell line)
- pENTR-ABCC1_STOP (RRID:Addgene_221423) (plasmid)
- Human SLC overexpression library (RRID:Addgene_213694) (plasmid)
- Human Transporter Knockout Library with UMIs (RRID:Addgene_221409) (plasmid)
- 1321N1 (RRID:CVCL_0110) (cell line)
- pENTR-ABCF2_STOP (RRID:Addgene_221425) (plasmid)
- HCT 116 (RRID:CVCL_0291) (cell line)
- pENTR-ABCB1_STOP (RRID:Addgene_221424) (plasmid)
- SK-MEL-28 (RRID:CVCL_0526) (cell line)
- Toronto KnockOut version 3 library (TKOv3) (RRID:Addgene_90294) (plasmid)
- lentiCas9-Blast (RRID:Addgene_52962) (plasmid)
- lentiCRISPR v2 (RRID:Addgene_52961) (plasmid)
- pLenti-UMI (RRID:Addgene_222694) (plasmid)
- pCW57.1 (RRID:Addgene_41393) (plasmid)
- pLentiCRISPRv4 (RRID:Addgene_221432) (plasmid)
- MDA-MB-468 (RRID:CVCL_0419) (cell line)
- 1321N1 (RRID:CVCL_0110) (cell line)
- HCT 116 (RRID:CVCL_0291) (cell line)
- Huh-7 (RRID:CVCL_0336) (cell line)
- SK-MEL-28 (RRID:CVCL_0526) (cell line)
- HAP1 (RRID:CVCL_Y019) (cell line)
- LS180 (RRID:CVCL_0397) (cell line)
- Toronto KnockOut version 3 library (TKOv3) (RRID:Addgene_90294) (plasmid)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- BRD3 antibody [2088C3a] (RRID:AB_868478)
- Anti-SMARCA2 antibody produced in rabbit (RRID:AB_10602406)
- alpha Tubulin antibody [DM1A] - Loading Control (RRID:AB_2241126)
- FAK Polyclonal Antibody (RRID:AB_2536313)
- Anti-BRD2 antibody (RRID:AB_2737409)
- PB1/BAF180 Antibody (RRID:AB_1078808)
- MDR1/ABCB1 (E1Y7B) Rabbit mAb #13342 (RRID:AB_2631176)
- Brd4 antibody [EPR5150(2)] (RRID:AB_11145462)
- BRG1 antibody [EPR3912] (RRID:AB_10889900)
- Mouse Anti-Human MRP1 (QCRL-1) Monoclonal, Unconjugated, Clone Qcrl-1 (RRID:AB_627964)
- Goat anti-Rabbit IgG H&L (IRDye® 800CW) preadsorbed (RRID:AB_2925189)
Associated grants
NonePublication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
BRD3 antibody [2088C3a] (antibody)
RRID:AB_868478
This monoclonal targets BRD3 antibody [2088C3a]
View all literature mentionsAnti-SMARCA2 antibody produced in rabbit (antibody)
RRID:AB_10602406
This polyclonal targets SMARCA2 antibody produced in rabbit
View all literature mentionsalpha Tubulin antibody [DM1A] - Loading Control (antibody)
RRID:AB_2241126
This monoclonal targets alpha Tubulin antibody [DM1A] - Loading Control
View all literature mentionsFAK Polyclonal Antibody (antibody)
RRID:AB_2536313
This unknown targets FAK
View all literature mentionsAnti-BRD2 antibody (antibody)
RRID:AB_2737409
This monoclonal targets BRD2
View all literature mentionsPB1/BAF180 Antibody (antibody)
RRID:AB_1078808
This unknown targets PBRM1
View all literature mentionsMDR1/ABCB1 (E1Y7B) Rabbit mAb #13342 (antibody)
RRID:AB_2631176
This monoclonal targets Human
View all literature mentionsBrd4 antibody [EPR5150(2)] (antibody)
RRID:AB_11145462
This monoclonal targets Brd4 antibody [EPR5150(2)]
View all literature mentionsBRG1 antibody [EPR3912] (antibody)
RRID:AB_10889900
This monoclonal targets BRG1 antibody [EPR3912]
View all literature mentionsMouse Anti-Human MRP1 (QCRL-1) Monoclonal, Unconjugated, Clone Qcrl-1 (antibody)
RRID:AB_627964
This monoclonal targets Human ABCC1
View all literature mentionsGoat anti-Rabbit IgG H&L (IRDye® 800CW) preadsorbed (antibody)
RRID:AB_2925189
This polyclonal secondary targets IgG (H+L)
View all literature mentionsHuh-7 (cell line)
RRID:CVCL_0336
Cell line Huh-7 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHAP1 (cell line)
RRID:CVCL_Y019
Cell line HAP1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMDA-MB-468 (cell line)
RRID:CVCL_0419
Cell line MDA-MB-468 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLS180 (cell line)
RRID:CVCL_0397
Cell line LS180 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHuman Transporter Knockout Library with UMIs (plasmid)
RRID:Addgene_221409
View all literature mentions
1321N1 (cell line)
RRID:CVCL_0110
Cell line 1321N1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHCT 116 (cell line)
RRID:CVCL_0291
Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSK-MEL-28 (cell line)
RRID:CVCL_0526
Cell line SK-MEL-28 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsToronto KnockOut version 3 library (TKOv3) (plasmid)
RRID:Addgene_90294
View all literature mentions
MDA-MB-468 (cell line)
RRID:CVCL_0419
Cell line MDA-MB-468 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions1321N1 (cell line)
RRID:CVCL_0110
Cell line 1321N1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHCT 116 (cell line)
RRID:CVCL_0291
Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHuh-7 (cell line)
RRID:CVCL_0336
Cell line Huh-7 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSK-MEL-28 (cell line)
RRID:CVCL_0526
Cell line SK-MEL-28 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHAP1 (cell line)
RRID:CVCL_Y019
Cell line HAP1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLS180 (cell line)
RRID:CVCL_0397
Cell line LS180 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsToronto KnockOut version 3 library (TKOv3) (plasmid)
RRID:Addgene_90294
View all literature mentions
