Drug discovery and development to overcome cancer evolution and drug resistance


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Paul Workman1
1The Institute of Cancer Research

Abstract

Over the last two decades we have progressed from traditional one-size-fits-all cytotoxic chemotherapy to discovery and successful use of innovative precision drugs that counteract effects of particular cancer genes that drive individual cancers — known as ‘oncogene addiction’. These include a number of drugs discovered in our Unit and progressed to the clinic, including the antihormonal agent abiraterone and inhibitors of oncogenic protein kinases and PI3 kinase. Despite substantial progress made, we and others have discovered many different ways by which resistance develops to both targeted and cytotoxic cancer drugs — including biochemical rewiring and genetic instability, cellular heterogeneity and Darwinian selection allowing evolution of resistant clones. Overcoming drug resistance is the greatest challenge that we now face in the cancer clinic — analogous to antibiotic resistance and resistance to HIV drugs.

Achieving substantial increases in survival and cure rates will require diverse innovative approaches including:

1) discovering drugs acting across a wider coverage of cancer targets;2) targeting non-oncogene addiction mechanisms including adaptive stress and proteostasis pathways;3) exploiting genetic instability, DNA repair pathways and other evolutionary mechanisms;4) activating a wider range of immune responses; and5) creative combinations of the above.

Examples from current work will be discussed.