- Email: [email protected]
Translational Research for Targeting Braf and Kras Mutant Cancers
Annals of Oncology 25 (Supplement 5): v6, 2014 doi:10.1093/annonc/mdu399.2
ESMO/JSMO Joint Symposium: ‘Translational research’ EJ
4
Hiromichi Ebi Division of Medical Oncology, Cancer Research Institute, Kanazawa University
abstracts
Oncogene addiction model in which cells are addicted to single protein have changed way to treat cancer patients. In lung adenocarcinoma, more than 60-70% of patients have a driver mutation that leads to oncogene addiction in cancer cells. In contrast, despite of massive efforts to sequence a number of tumor samples, only a few driver mutations are identified so far in colorectal cancer: KRAS, NRAS, PIK3CA, BRAF. Therefore, we need to seek strategies to treat patients harboring these mutations.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_5/v6/2240126 by guest on 24 October 2019
TRANSLATIONAL RESEARCH FOR TARGETING BRAF AND KRAS MUTANT CANCERS
When a molecular targeting agent works, both PI3K-AKT and MAPK signaling are downregulated and that leads to apoptosis in cancer cells. If we can identify key mechanisms to suppress these signaling, we may apply it to treat patients in KRAS and BRAF mutant cancers. In BRAF mutant cancer, BRAF inhibitor vemurafenib was approved by FDA to treat melanoma with BRAFV600E mutation. However, single treatment of vemurafenib showed minimal activity in phase I clinical trial for the patients with BRAF mutant colorectal cancers. Using biochemical analysis, we have identified that vemurafenib treatment upregulate EGFR signaling and maintain MAPK signaling. Combined inhibition of EGFR and BRAF signaling is effective in BRAF mutant colorectal cancer xenograft. These pre-clinical data spurred clinical trials combing anti-EGFR antibody with vemurafenib, which has been shown promising results so far. In comparison to promising treatment strategy to BRAF mutant cancer, treatment strategies to KRAS mutant cancers are not established yet. Targeting key pathways in KRAS mutant cancers show some promise in preclinical model, however, there are still many obstacles to introduce these therapies into clinic. Current treatment strategies to target KRAS will be summarized in the presentation. Finally, a couple of possible collaboration between physician-scientist, basic scientist, pharmaceutical company, and clinical oncologist would be proposed.
ESMO/JSMO Joint Symposium: ‘Translational research’ EJ
4
Hiromichi Ebi Division of Medical Oncology, Cancer Research Institute, Kanazawa University
abstracts
Oncogene addiction model in which cells are addicted to single protein have changed way to treat cancer patients. In lung adenocarcinoma, more than 60-70% of patients have a driver mutation that leads to oncogene addiction in cancer cells. In contrast, despite of massive efforts to sequence a number of tumor samples, only a few driver mutations are identified so far in colorectal cancer: KRAS, NRAS, PIK3CA, BRAF. Therefore, we need to seek strategies to treat patients harboring these mutations.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_5/v6/2240126 by guest on 24 October 2019
TRANSLATIONAL RESEARCH FOR TARGETING BRAF AND KRAS MUTANT CANCERS
When a molecular targeting agent works, both PI3K-AKT and MAPK signaling are downregulated and that leads to apoptosis in cancer cells. If we can identify key mechanisms to suppress these signaling, we may apply it to treat patients in KRAS and BRAF mutant cancers. In BRAF mutant cancer, BRAF inhibitor vemurafenib was approved by FDA to treat melanoma with BRAFV600E mutation. However, single treatment of vemurafenib showed minimal activity in phase I clinical trial for the patients with BRAF mutant colorectal cancers. Using biochemical analysis, we have identified that vemurafenib treatment upregulate EGFR signaling and maintain MAPK signaling. Combined inhibition of EGFR and BRAF signaling is effective in BRAF mutant colorectal cancer xenograft. These pre-clinical data spurred clinical trials combing anti-EGFR antibody with vemurafenib, which has been shown promising results so far. In comparison to promising treatment strategy to BRAF mutant cancer, treatment strategies to KRAS mutant cancers are not established yet. Targeting key pathways in KRAS mutant cancers show some promise in preclinical model, however, there are still many obstacles to introduce these therapies into clinic. Current treatment strategies to target KRAS will be summarized in the presentation. Finally, a couple of possible collaboration between physician-scientist, basic scientist, pharmaceutical company, and clinical oncologist would be proposed.