Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth.
RAS mutations are the most common gain-of-function change in human cancer and promise to be a critical therapy target. As a new approach, we have used a surrogate to drug the 'undruggable' (that is, RAS-effector protein-protein interactions inside cancer cells) in pre-clinical mouse models of RAS-dependent cancers. Using this novel reagent, we have specifically targeted RAS signalling in a transgenic mouse model of lung cancer by directly blockading RAS-effector interactions with an antibody fragment that binds to activated RAS, and show that the interaction of RAS and effectors, such as phosphoinositide 3-kinase and RAF, is necessary for tumour initiation. Further, interference with oncogenic RAS-effector interactions result in control of tumour growth in human cancer cells but, crucially, does not necessarily cause tumour regression. These findings support the concept that ablating RAS-dependent signalling in cancer will have chemo-preventive effects that confer a chronic state in cancer and suggest that mutant RAS-targeted therapies may require conjoint targeting of other molecules and/or current cancer therapeutic strategies (for example, radiotherapy and chemotherapy) to be curative. In this context, our findings suggest that the oncogene addiction model is not universally correct in its central thesis that cancer cell death is inevitable after loss of oncogenic protein function.
Tanaka
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Leeds Institute of Molecular Medicine, Section of Experimental Therapeutics, St James's University Hospital, University of Leeds, Leeds, UK.
Rabbitts
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D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism* / Q000494:pharmacology
D018631:ras Proteins