So I gave a talk on synthetic lethality in a special symposium where I focused on the current therapeutic and biomarker strategies, but also discussed the potential progress, pitfalls, and the promise that this very exciting class of agents is currently showing in this particular strategy in cancer medicine is showing, particularly in novel clinical translation. I first discuss why it’s important to think about synthetic lethal approaches in targeting the untapped cancer lesions...
So I gave a talk on synthetic lethality in a special symposium where I focused on the current therapeutic and biomarker strategies, but also discussed the potential progress, pitfalls, and the promise that this very exciting class of agents is currently showing in this particular strategy in cancer medicine is showing, particularly in novel clinical translation. I first discuss why it’s important to think about synthetic lethal approaches in targeting the untapped cancer lesions. For ever so long, for example, over the past 20 years or so, the main focus of precision medicine has been on gain-of-function targetable alterations, such as EGFR mutations and HER2-amplified tumors. And this has really led to a number of drugs being approved. But we also need to start thinking about the untapped cancer lesions. For example, the undruggable gain-of-function alterations such as CCNE1 amplification and also loss-of-function alterations to go beyond BRCA1 and BRCA2 mutations. And this is a huge untapped space in cancer medicine and will allow us to really raise that bar in cancer medicine. And it will also allow physicians to use biomarker-driven patient selection to really guide the clinical development of multiple different anti-tumor agents. And there are now multiple examples of synthetic lethal strategies that go beyond PARP inhibitors and different HRR mutations such as BRCA1, BRCA2, PALB2, or RAD51C mutations. But also we have shown potential for Werner helicase inhibitors in MSI cancers, ATR inhibitors in ATM loss of function alterations, PKM2 inhibitors with CCNE1 amplified tumors, SMARCA2 inhibitors such as degraders and small molecules, and SMARCA4 mutation tumors, and also MTA co-operative PRMT5 inhibitors in ATM loss cancers.
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