G Saturno1, F Lopes2, I Niculescu-Duvaz3, D Niculescu-Duvaz2, A Zambon3, L Davies3, L Johnson3, N Preece3, R Lee1, A Viros1, D Holovanchuk1, M Pedersen4, R McLeary2, P Lorigan5, N Dhomen1, C Fisher6, U Banerji6, E Dean5, M G Krebs5, M Gore6, J Larkin6, R Marais7, C Springer8. 1. Molecular Oncology Group, Cancer Research UK Manchester Institute, the University of Manchester, Alderley Park, Manchester, UK. 2. Drug Discovery Unit, Cancer Research UK Manchester Institute, the University of Manchester, Alderley Park, Manchester, UK; Gene and Oncogene Targeting Team, CR-UK Cancer Therapeutics Unit, the Institute of Cancer Research, London, UK. 3. Gene and Oncogene Targeting Team, CR-UK Cancer Therapeutics Unit, the Institute of Cancer Research, London, UK. 4. Targeted Therapy Team, the Institute of Cancer Research, London, UK. 5. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 6. The Royal Marsden NHS Foundation Trust, London, UK. 7. Molecular Oncology Group, Cancer Research UK Manchester Institute, the University of Manchester, Alderley Park, Manchester, UK. Electronic address: richard.marais@manchester.ac.uk. 8. Drug Discovery Unit, Cancer Research UK Manchester Institute, the University of Manchester, Alderley Park, Manchester, UK; Gene and Oncogene Targeting Team, CR-UK Cancer Therapeutics Unit, the Institute of Cancer Research, London, UK. Electronic address: caroline.springer@manchester.ac.uk.
Abstract
BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.
BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.
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