Search

Background FMS-like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis, and FLT3-associated molecular alterations are an established predictor for the treatment with FLT3 inhibitors in acute myeloid leukemia. However, the oncogenic role of FLT3 amplification (amp) in patients (pts) with metastatic colorectal cancer (mCRC) has not yet been well established. Methods Tumor tissue samples from 2,329 mCRC pts were sequenced using next-generation sequencing (NGS) with Oncomine Comprehensive Assay in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN). Clinicopathological features, co-altered genes, prognosis and regorafenib efficacy on FLT3 amp (defined as copy number ≥ 7.0) vs. non-FLT3 amp mCRC were investigated. Results Between Apr 2015 and Jun 2018, a total of 85 pts (3.6%) with mCRC with FLT3 amp were observed. There were no clear differences in baseline characteristics between pts with or without FLT3 amp. The enrichment of TP53 mutation in FLT3 amp mCRC was observed more frequently than non-FLT3 amp (74.1% vs. 64.7%, P = 0.08), but RAS mutation frequency was similar in both (48.2% vs. 42.8%, P = 0.31). In contrast, activating alterations in BRAF (1.1% vs. 7.1%, P = 0.053) and PIK3CA (1.1% vs 7.0%, P = 0.03) mutations were both less frequent in FLT3 amp vs. non-FLT3 amp mCRC. Median OS from 1st-line chemotherapy in FLT3 amp mCRC was significantly shorter than those in non-FLT3 amp (30.2 vs. 43.4 months, P = 0.002). Furthermore, in 20 pts receiving regorafenib, a multikinase inhibitor with a mild inhibitory activity of FLT3, the disease control rate (DCR) was higher in FLT3 amp mCRC pts (n = 7) compared with non-FLT3 amp (57.1% vs. 23.0 %, P = 0.13). Conclusions FLT3 amp was associated with a significantly worse survival and a higher DCR from regorafenib, suggesting it has a distinct oncogenic role in mCRC. Further investigation of the oncogenic role of FLT3 amp in mCRC is warranted in clinical trials. Clinical trial identification UMIN000016344. Legal entity responsible for the study SCRUM-Japan. Funding 17 SCRUM-Japan Collaborating Pharmaceutical Companies, AMED, NCC. Disclosure H. Taniguchi: Research grant / Funding (self): Takeda; Advisory / Consultancy: Chugai; Advisory / Consultancy: Taiho. T. Kato: Honoraria (self): Chugai Pharmaceutical; Advisory / Consultancy: Takeda; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Yakult Honsya. S. Yuki: Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Bayer Yakuhin; Speaker Bureau / Expert testimony: Ono Pharmaceutical; Speaker Bureau / Expert testimony: Pharma International; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Takeda Pharmaceutical; Speaker Bureau / Expert testimony: Eli Lilly Japan; Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony: Merck Biopharma. T. Masuishi: Honoraria (self): Eli Lilly; Honoraria (self): Chugai Pharma; Honoraria (self): Merck Serono; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Yakult Honsya. K. Kato: Research grant / Funding (self): Shionogi; Research grant / Funding (self): Ono Pharmaceutical; Research grant / Funding (self): Merck Serono. N. Izawa: Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck Serono. T. Moriwaki: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Yakult Honsha; Research grant / Funding (institution): Eisai; Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony: Merck Serono; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Liliy Japan; Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Ono Pharmaceutical. Y. Kagawa: Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Sanofi; Speaker Bureau / Expert testimony: Taiho. W. Okamoto: Research grant / Funding (institution): MSD. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. K. Yamazaki: Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Taiho Pharma; Honoraria (self): Bayer Yakuhin. T. Yoshino: Research grant / Funding (institution): Chugai pharma; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Sumitomo Dainippon pharma; Research grant / Funding (institution): Glaxo SmithKline. All other authors have declared no conflicts of interest.

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. 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.

BRAF mutations occur in 10–15% of colorectal cancers (CRCs) and confer adverse outcomes. Whereas RAF inhibitors such as vemurafenib (PLX4032) have shown effectiveness in melanoma patients with BRAF mutation, they are surprisingly ineffective in BRAF mutant CRCs, and the reason for this disparity remains unclear. Here, we identified a potential mechanism of de novo resistance in CRC tumors by utilizing biochemical and pathological analyses. Compared with BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P-ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re-activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRCs shown remarkably higher expression of phospho-EGFR compared with BRAF mutant melanomas, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells and markedly improved efficacy in vitro and in vivo. These findings support to start a clinical trial of combined RAF and EGFR inhibition for the treatment of BRAF mutant CRC patients.