Impact of endosomal recycling inhibitors on drug resistant and immune tolerant breast cancers

Breast cancer (BC) is the most common and frequent of all the cancers, accounting for about 25% of all the cases of cancer detected in women annually. There are a number of approved drugs on the market that have been developed or repurposed for the treatment of BC. However, a recurrent problem faced in the clinic is the emergence of drug resistance, which can be intrinsic or acquired. Prolonged periods of chemotherapeutics and targeted therapy have resulted in the development of acquired resistance through a number of different adaptations. This project focuses on resistance developed by various sub-types of breast cancer cells through drug-therapy-induced senescence. Previous studies have reported the cytoprotective nature of this cell cycle arrest phenomenon upon prolonged exposure to targeted- and chemotherapeutics. This study investigates specific molecular mechanisms governing therapy-induced senescence, the impact it has on the membrane trafficking of iron transporters, and the potential repurposing of endosomal recycling inhibitors (ERIs) to target these drug-tolerant cells. Additionally, we examined the effects of ERIs on the total protein and surface levels of immune checkpoint proteins. This was done by targeting the recycling of the glycoprotein PDL1, which is expressed on the surface of some tumour cells and binds to its cognate receptors on the surface of T cells. PDL1-PD1 binding leads to T cell inactivation. A number of ERIs were used to determine their impact on the levels of PDL1.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2024

Author dc:creator

• Chembukavu, Suraj Narayanan

Advisor dc:contributor.advisor

• Lindsay, Andrew

• Breast cancer
• Drug resistance
• Therapy-induced senescence
• Doxorubicin
• Lapatinib
• Primaquine
• Monensin
• Endosomal recycling pathway
• Iron transporters
• Transferrin receptor
• Ferritin
• Senolytics

Statement dc:rights

• © 2024, Suraj Narayanan Chembukavu.

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/10468/16431

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/16431