Abstract
Lung cancer is a heterogeneous disease consisting of multiple histological subtypes each driven by unique genetic alterations. Despite the development of targeted therapies that inhibit the oncogenic mutations driving a subset of lung cancer cases, there is a paucity of effective treatments for the majority of lung cancer patients and new strategies are urgently needed. In recent years, the concept of synthetic lethality has been established as an effective approach for discovering novel cancer-specific targets as well as a method to improve the efficacy of existing drugs which provide partial but insufficient benefits for patients. In this review, we discuss the concept of synthetic lethality, the various types of synthetic lethal interactions in the context of oncology and the approaches used to identify these interactions, including recent advances that have transformed the ability to discover novel synthetic lethal combinations on a global scale. Lastly, we describe the specific synthetic lethal interactions identified in lung cancer to date and explore the pharmacological challenges and considerations in translating these discoveries to the clinic.
Highlights
The concept of synthetic lethality and approaches for uncovering interactions in cancer cells Synthetic lethality is traditionally defined as a condition where simultaneous mutation in two genes – but not either alone - leads to cell death [12, 13]
Drug combinations are designed with the ultimate goal of curing the disease, but more frequently, significant improvements in treatment outcomes are achieved through synergy, which we argue is equivalent to a synthetic sick effect at the cell population level in the context of cancer biology
Other synthetic lethal partners that have been identified through RNAi screening within an activated KRAS background include STK33, TBK1, WT1, CDK1, CDK4, GATA2, and Snail2, studies conducted primarily using colon and lung cancer cells [58,59,60,61,62,63,64]
Summary
The concept of synthetic lethality and approaches for uncovering interactions in cancer cells Synthetic lethality is traditionally defined as a condition where simultaneous mutation in two genes – but not either alone - leads to cell death [12, 13]. Types of synthetic lethality and identified interactions in lung cancer The transformation of normal cells to cancer cells involves a step-wise evolution: a progressive series of genetic mutations that allow cells to acquire the hallmarks of cancer over time and become malignant [35] These genetic changes cause deficiencies in, or addiction to, certain cellular processes and biological pathways that initiate transformation and are prime targets for therapeutic intervention. Based on differential gene expression analyses, Wang and Simon proposed a list of 98 candidate genes that, when suppressed, may induce synthetic lethality in p53-deficient cancers [40] We define such a strategy as LOF/LOF as it involves inhibiting a gene/pathway/function in the background of genetic or pharmacological inactivation of another gene to induce synthetic lethality. The discovery of this truly synthetic lethal interaction (by definition) has revolutionized our approach to the treatment of BRCA-associated cancers and served as the paradigm for uncovering other synthetic lethal interactions
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