MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

ABSTRACTPROTACs (Proteolysis-Targeting Chimeras) represent a promising new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to PROTACs remains poorly understood. Using proteomics, we discovered acquired and intrinsic resistance to PROTACs in cancer cells can be mediated by upregulation of the drug efflux pump MDR1. PROTAC-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, co-treatment of MDR1-overexpressing colorectal cancer cells with MEK1/2 or KRASG12C degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 and ErbB receptor activity. Together, our findings suggest that concurrent blockade of MDR1 will likely be required in combination with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

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Comparative Study of the Sensitivities of Cancer Cells to Doxorubicin, and Relationships between the Effect of the Drug-Efflux Pump P-gp

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b14-00529 ◽

2014 ◽

Vol 37 (12) ◽

pp. 1926-1935 ◽

Cited By ~ 24

Author(s):

Golam Kibria ◽

Hiroto Hatakeyama ◽

Kosuke Akiyama ◽

Kyoko Hida ◽

Hideyoshi Harashima

Keyword(s):

Comparative Study ◽

Cancer Cells ◽

Efflux Pump ◽

Drug Efflux ◽

Drug Efflux Pump

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ID:2037 Molecular mechanisms underlying resistance to MEK1/2 inhibitor in BRAF-mutated colorectal cancer

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.276 ◽

2017 ◽

Vol 4 (S) ◽

pp. 68

Author(s):

Hong-Quan Duong

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Acquired Resistance ◽

Genetic Alterations ◽

Scaffold Protein ◽

Colorectal Carcinomas ◽

Intrinsic Resistance ◽

Oncogenic Signaling ◽

Colorectal Cancer Cells

Colorectal carcinomas are characterized by multiple genetic alterations, including constitutive Wnt activity and gain-of-function mutations in K-RAS and B-RAF. BRAF encodes a Ser/Thr kinase acting in the Ras/MEK/ERK pathway and the V600E mutation found in 11% of colorectal cancers renders this kinase constitutively active. B-RAF mutated colorectal carcinomas represents a very aggressive entity with a poor prognosis. Understanding the molecular mechanisms activated downstream of mutated B-RAF is urgently needed to design new therapeutic avenues to treat B-ARF mutated colorectal carcinomas and to circumvent resistance to therapies targeting the Ras/Raf/MEK1/ERK1/2 pathway. In a search for candidates that critically contribute to both intrinsic and acquired resistance to MEK1 inhibition in B-RAF mutated colorectal cancer cells, we identified one scaffold protein whose expression is driven by both NF-kB and AP-1 families of transcription factors. This scaffold protein promotes the expression of HER2 and HER3 in colorectal cancer cells subjected to MEK1 or B-RAF inhibition (Selumetinib and Vemurafenib, respectively) and, as such, is critically involved in the intrinsic resistance to these targeted therapies. The same scaffold protein is also strongly induced in B-RAF but not K-RAS mutated colorectal cancer cells showing acquired resistance to MEK1 inhibition. Interfering with the expression of this scaffold protein circumvents both intrinsic and acquired resistance to Selumetinib in B-RAF mutated colorectal cancer cells. Our study defines a new molecular actor critically involved in oncogenic signaling pathways triggered by mutated B-RAF. Our study also defineS new combinatory therapies to better treat B-RAF-mutated colorectal carcinomas.

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Human hepatocellular carcinoma cell lines exhibit multidrug resistance unrelated to MRD1 gene expression

Journal of Cell Science ◽

10.1242/jcs.98.3.317 ◽

1991 ◽

Vol 98 (3) ◽

pp. 317-322

Author(s):

D.W. Shen ◽

Y.G. Lu ◽

K.V. Chin ◽

I. Pastan ◽

M.M. Gottesman

Keyword(s):

Hepatocellular Carcinoma ◽

Multidrug Resistance ◽

Cancer Cells ◽

Cell Lines ◽

Actinomycin D ◽

Efflux Pump ◽

Mdr1 Gene ◽

Drug Efflux ◽

P Glycoprotein ◽

Drug Efflux Pump

Multidrug resistance of human cancer cells may result from expression of P-glycoprotein, the product of the MRD1 gene, acting as an energy-dependent drug efflux pump. However, direct evidence that expression of the MDR1 gene contributes to the multidrug resistance of human liver carcinomas has not been established. In this study, we tested five cell lines derived from human hepatocellular carcinomas for sensitivity to a variety of drugs used widely as anticancer agents; these included vinblastine, doxorubicin, actinomycin D, mitomycin C, 5-fluorouracil, 6-mercaptopurine, melphalan, methotrexate, cis-platinum and etoposide (VP-16). All five hepatoma cell lines were resistant at different levels to these chemicals compared to human KB cells. Although it has been demonstrated that resistance to vinblastine, colchicine, doxorubicin and actinomycin D in human multidrug-resistant cells is associated with overexpression of P-glycoprotein, very little expression of P-glycoprotein was found in these human hepatoma cells. Neither verapamil nor quinidine, inhibitors of the drug efflux pump, were able to overcome multidrug resistance in hepatoma cells. These results indicate that the multidrug resistance phenotype in human hepatocellular carcinoma cells cannot be attributed to expression of the MDR1 gene, but that novel mechanisms may account for the resistance of these cancer cells.

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Chromosomal imbalances associated with acquired resistance to fluoropyrimidines in human colorectal cancer cells

European Journal of Cancer ◽

10.1016/s0959-8049(03)00028-5 ◽

2003 ◽

Vol 39 (7) ◽

pp. 975-980 ◽

Cited By ~ 6

Author(s):

S Hidaka ◽

T Yasutake ◽

M Fukushima ◽

H Yano ◽

M Haseba ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Acquired Resistance ◽

Human Colorectal Cancer ◽

Chromosomal Imbalances ◽

Colorectal Cancer Cells ◽

Human Colorectal Cancer Cells

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P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells

Life Sciences ◽

10.1016/0024-3205(92)90537-y ◽

1992 ◽

Vol 51 (18) ◽

pp. 1427-1437 ◽

Cited By ~ 197

Author(s):

Akira Tsuji ◽

Tetsuya Terasaki ◽

Yasushi Takabatake ◽

Yoshiyuki Tenda ◽

Ikumi Tamai ◽

...

Keyword(s):

Endothelial Cells ◽

Efflux Pump ◽

Bovine Brain ◽

Drug Efflux ◽

Brain Capillary ◽

Brain Capillary Endothelial Cells ◽

P Glycoprotein ◽

Capillary Endothelial Cells ◽

Drug Efflux Pump

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Structure-property correlation in gallic acid and 4-cyanopyridine cocrystal and binding studies with drug efflux pump in bacteria

Journal of Molecular Structure ◽

10.1016/j.molstruc.2020.129279 ◽

2021 ◽

Vol 1225 ◽

pp. 129279

Author(s):

Shyam Goswami ◽

Arabinda Ghosh ◽

Karmajyoti Borah ◽

Anupam Mahanta ◽

Ankur K Guha ◽

...

Keyword(s):

Gallic Acid ◽

Efflux Pump ◽

Drug Efflux ◽

Structure Property ◽

Binding Studies ◽

Property Correlation ◽

Drug Efflux Pump

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Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

MicrobiologyOpen ◽

10.1002/mbo3.212 ◽

2014 ◽

Vol 3 (6) ◽

pp. 885-896 ◽

Cited By ~ 34

Author(s):

Thelma Ohene‐Agyei ◽

Rumana Mowla ◽

Taufiq Rahman ◽

Henrietta Venter

Keyword(s):

Antibacterial Activity ◽

Efflux Pump ◽

Drug Efflux ◽

Drug Efflux Pump

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SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

Science Signaling ◽

10.1126/scisignal.aay6077 ◽

2020 ◽

Vol 13 (654) ◽

pp. eaay6077

Author(s):

Apoorva Bhattacharya ◽

Shravanti Mukherjee ◽

Poulami Khan ◽

Shruti Banerjee ◽

Apratim Dutta ◽

...

Keyword(s):

Efflux Pump ◽

Chemotherapy Resistance ◽

Cooperative Interaction ◽

Drug Efflux ◽

Cancer Stemness ◽

Gene Encoding ◽

Pluripotency Factors ◽

Tumor Bearing ◽

Drug Efflux Pumps ◽

Drug Efflux Pump

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

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