Small cell lung cancer (SCLC) has been defined as a "recalcitrant" disease and better treatments are urgently needed. High mutational burden, oncogene induced replication stress and universal loss of G1 checkpoints in SCLC validate it for treatment with DNA damage response inhibitors (DDRi). I investigated the effects of the PARP inhibitor olaparib and the WEE1 inhibitor AZD1775 on SCLC preclinical models. PARP is a crucial regulator of several DNA damage pathways, whilst WEE1 controls CDK activity and cell cycle progression. Their dual inhibition has emerged as a promising strategy to drive SCLC cells beyond their survival threshold. In this thesis, I present data that supports the exploitation of circulating tumour cell patient-derived explant models (CDX) as a platform to study the response of SCLC patients to several DDRi and to identify biomarkers of treatment response. I demonstrated that CDX-derived cells can be cultured successfully ex vivo, and retain most of the features of the donor CDX tumour. In particular, the majority of CDX cultures I derived were able to predict the original CDX's in vivo response to therapies. I utilised the CDX culture platform to investigate the potential of combining AZD1775 and olaparib. Screening of a panel of 20 CDX cultures demonstrated disparate responses, highlighting the need for predictive biomarkers of response to stratify patients in clinical trials. However, the investigation of cell cycle checkpoints and DNA damage repair pathways revealed a high degree of heterogeneity between individual CDX models. This challenged the identification of a universal response biomarker, and highlighted the need for a better understanding of the molecular mechanisms underpinning these treatment responses. Ex vivo screens of different DDRi combinations identified a group of CDX resistant to most combinations tested. These models have an intrinsic ability to survive despite the induction of substantial DNA damage. AZD2811, an inhibitor of the mitotic regulator Aurora kinase B, was highly cytotoxic in some of the otherwise resistant cultures, making this drug a promising alternative treatment for chemorefractory SCLC patients. Overall, this thesis shows that CDX cultures are a faithful model to study SCLC and confirms DDRi as a promising therapeutic strategy for SCLC patients.
|Date of Award||1 Aug 2020|
- The University of Manchester
|Supervisor||Caroline Dive (Supervisor) & Claus Jorgensen (Supervisor)|
- DNA damage response
- ex vivo culture