PO-338 Tumour heterogeneity underlies differential cisplatin sensitivity in mouse models of SCLC

Abstract

IntroductionSCLC is the most aggressive subtype of lung cancer for which no effective therapy exists. Disease is frequently diagnosed at an extensive stage due to early and widespread metastatic dissemination. It is characterised by a remarkable initial response to chemotherapy followed, almost invariably, by development of resistant disease. Mechanisms of initial sensitivity and of subsequent resistance are not understood.Material and methodsWe have developed several mouse models of SCLC which recapitulate human disease and model key genetic alterations found in patients. The animal models Rb1/Trp53 Mycl and Rb1/Trp53 Nfib were subjected to cisplatin treatment, treated and untreated tumour populations were compared using multi-panel histopathology and proteomic profiling of paraffin-derived material.Results and discussionsCareful characterisation of Rb1/Trp53 Mycl mouse model revealed significant tumour heterogeneity. Neuroendocrine tumours developed throughout the pulmonary tree and were invariably positive for E-cadherin (CDH1). Over time, tumours located within main bronchi gave rise to major invasive, highly proliferative dissemination that spread mainly via lymphatic system. Disseminating cells lost CDH1 expression while expressing high level of transcription factor NFIB. In contrast, lesions originating more distally, and those within the bronchio-alveolar duct junction region, remained CDH1hi. Importantly, following cisplatin treatment, CDH1neg population was almost fully eliminated, leaving behind CDH1hitumors. No survival advantage was observed, likely due to cisplatin-associated toxicity.We showed previously that Rb1/Trp53 Nfib animals have predominantly CDH1neg dissemination-like tumour population, which is therefore likely to be cisplatin-sensitive. Indeed, treatment of Rb1/Trp53 Nfib animals resulted in a significant survival advantage. We next carried out proteomic analysis of treated and untreated Rb1/Trp53 Nfibtumours which revealed a change in protein marker profile. Treated tumours showed reduced expression of cell cycle related proteins, a shift from neuronal towards epithelial phenotype, and elevated expression of DNA damage repair proteins.ConclusionSCLC tumours in the mouse show population heterogeneity which appears, as might be the case in humans, to be one of the underlying mechanisms of differential sensitivity to cisplatin.