Inhibition of the endosomal recycling pathway to overcome resistance to cancer therapies

Cancer is a major public health threat with incidence and mortality rates continuing to rise every year. Breast and prostate cancer are the most diagnosed cancers in women and men, respectively. Both cancers account for roughly 30% of all cancers diagnosed in each sex. Despite the continuous development of new therapies, drug resistance is a growing problem and is a major cause of cancer treatment failure, accounting for many cancer recurrences and deaths. Therefore, new drugs and treatment regimens are urgently required to overcome this resistance. Recent findings from our own lab and others have found that inhibition of the endosomal recycling pathway may be a promising strategy to downregulate clinically relevant cell surface proteins and to overcome drug resistance. This thesis focuses on two clinically relevant hormone receptors that are strongly linked to the development and progression of breast and prostate cancer linked to disease development and progression, the estrogen receptor alpha and the androgen receptor. The aim of this project was to confirm data obtained from a reverse-phase protein array (RPPA) study performed by our lab that found that the endosomal recycling inhibitor primaquine downregulates ER-α and AR expression. We used Western blot, quantitative RT-PCR, and immunofluorescence microscopy to confirm the RPPA results. We found that another endosomal recycling inhibitor, monensin, also potently downregulates these hormone receptors and that both inhibitors synergise with tamoxifen and enzalutamide, standard-of-care therapies for breast and prostate cancer. Keywords Cancer, prostate, breast, androgen receptor, estrogen receptor, endosomal recycling pathway, primaquine, monensin, drug resistance, tamoxifen, lapatinib, enzalutamide, synergy.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2022

Author dc:creator

• Fletcher, Kelsey

Advisor dc:contributor.advisor

• Lindsay, Andrew

• Cancer
• Prostate
• Breast
• Androgen receptor
• Estrogen receptor
• Endosomal recycling pathway
• Primaquine
• Monensin
• Drug resistance
• Tamoxifen
• Lapatinib
• Enzalutamide
• Synergy

Statement dc:rights

• © 2022, Kelsey Fletcher.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/14092

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/14092