Synthetic lethality in lung cancer and translation to clinical therapies.
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.
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada. aleung@bccrc.ca.|Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. aleung@bccrc.ca.
Ada W Y
AW
Leung
Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.|Integrative Oncology, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada.
Tanya
T
de Silva
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.|Centre for Drug Research and Development, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Marcel B
MB
Bally
Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. wlockwood@bccrc.ca.|Integrative Oncology, BC Cancer Research Centre, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada. wlockwood@bccrc.ca.
William W
WW
Lockwood
Combination treatments; Drug-drug interactions; Lung cancer; Synergy; Synthetic lethality
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