Abstract
Both lung cancer and melanoma are of significant concern to New Zealanders and the global community due to their high mortality rates. Oncogene-driven cancers resulting from mutations in genes regulating cell growth and division can be treated with targeted therapies. These treatments are more effective than traditional chemotherapy as they can target these oncogenic mutations and lead to improved cancer outcomes in patients. However, targeted therapies are not curative and in a majority of cases relapse inevitably occurs due to genetic, non-genetic and pharmacokinetic failure. Drug-tolerant persister cells (DTPs) are a subset of slow-cycling cells that survive anti-cancer treatments often preceding relapse, resistance and further metastasis in cancer. DTPs evade targeted therapy treatment but are not genetically resistant cells as upon treatment discontinuation can regain sensitivity to treatment. However, they are thought to provide a reservoir from which genetic resistance to emerges. Therefore, understanding this persister state and its mechanisms of survival will allow us to prevent or delay resistance, relapse and further metastasis. A factor demonstrated to contribute to persister cells survival, is the transition from glycolysis to mitochondrial oxidative respiration (OXPHOS). So, targeting respiration in DTPs may be a key to prevent relapse within cancer. Previous studies have shown utilizing targeted therapies alongside drugs which target respiration results in a reduction of DTPs and prevented metastasis and further cell growth. Bedaquiline, a drug approved in New Zealand for the treatment of tuberculosis, has been shown to target the mitochondrial ATP-synthase preventing cell growth and metastasis in breast and lung cancer cell lines. Therefore, I hypothesised bedaquiline would inhibit the energy metabolism of DTPs and in combination with targeted therapies will prevent the survival of DTPs or extend the time until relapse occurs. Bedaquiline was tested alone and alongside osimertinib and vemurafenib within PC9 lung adenocarcinoma and A375 melanoma cells respectively. Bedaquiline alone partially inhibits PC9 and A375 cell growth, and in combination with targeted therapies was more effective at reducing cell growth than targeted therapy treatment alone. Combination treatment also altered the mRNA expression of DTP and mitophagy markers within both cell lines. Long-term treated cells revealed combination treatment greatly reduced the survival of DTPs compared to targeted therapies alone. As well as gene expression changes, cells displayed changes in cell morphology within targeted therapy and combination groups. These preliminary findings suggest that combining bedaquiline with targeted therapies has the potential to inhibit the survival of DTPs and contribute to improved patient outcomes.