Lung cancer is by far the commonest cause of cancer-related death. Small cell lung cancer (SCLC) is a highly malignant neuroendocrine tumour that makes up 15-20% of the 9,700 Australians dying every year from lung cancer. Although SCLC is often sensitive to platinum-based chemotherapy at presentation, a secondary drug-resistant recurrence occurs in almost all cases, leading to a dismal overall 5-year survival rate of less than 5%. Large scale genomics analysis has revealed almost universal inactivation of TP53 and RB1, however this is always in combination with other oncogenic mutations including mutations to the MYC family of oncogenes which is observed in around 20% of SCLC tumours.
The lack of surgical intervention in SCLC has made tissue and patient derived xenograft models scarce. Therefore, we are heavily reliant on accurate genetically engineered mouse models (GEMM) to identify new therapeutic approaches. We developed a GEMM of Myc driven SCLC. Using a GEMM with only MYC overexpression, we showed that amplification of MYC throughout the lung leads to SCLC. However, when MYC overexpression is restricted to specific cell types we observe adenocarcinoma (Clara and Alveolar Type 2 activated cells). Importantly when we combine MYC over-expression with pRb1 and p53 loss to closely resemble the genetics of the human disease we observe an aggressive and metastatic SCLC.