Identifying New Treatments for Platinum Resistant Small Cell Lung Cancer

Lung cancer is by far the commonest cause of cancer-related death [1]. 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 [2]. Although SCLC is often sensitive to platinum-based chemotherapy, a lethal drug-resistant recurrence occurs in almost all cases, leading to an overall 5-year survival rate of less than 5% [3]. Despite intensive efforts in genome sequencing and experimental therapeutics, no new therapy for SCLC has been identified in the last 3 decades [4]. This ongoing unmet clinical need reflects a critical knowledge gap in our understanding of this disease at a preclinical and translational level.
Although inactivating mutations in both TP53 and RB1 are characteristic of SCLC [5], the variable contributions of cooperating oncogenic events, smoking-induced mutation patterns and chromosomal instability are poorly understood. In this application, we will explore the biological and therapeutic implications of aberrant MYC signalling, which is amplified in 10-36% of SCLC [6] [7]. Remarkably, the functional significance of MYC signalling in SCLC is restricted to anecdotal reports showing that SCLC cell lines derived from patients with relapsed/resistant disease are more likely to harbor amplification in MYC, MYCN or MYCL1 [7]. Although oncogenic MYC signalling has re-emerged as one of the most important biological and therapeutic challenges in cancer biology, its importance in SCLC remains largely unexplored. We hypothesize that elevated MYC expression drives platinum resistance in SCLC which represents a vulnerability that can be exploited by targeting MYC-dependent activities.