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J. Hamamoto
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-012 - Characterization of the Efficacies of Osimertinib and Nazartinib against Cells Expressing Epidermal Growth Factor Receptor Mutations (ID 8067)
09:30 - 09:30 | Author(s): J. Hamamoto
- Abstract
Background:
A significant subgroup of non-small cell lung cancers harbor epidermal growth factor receptor (EGFR) mutations. Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to first- and second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFR-TKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs. The present study used this approach to characterize the efficacies of third-generation EGFR-TKIs and compare them with those of other EGFR-TKIs such as erlotinib and afatinib.
Method:
We evaluated the drug sensitivity and EGFR downstream signals of human lung cancer cell lines (PC9, H3255, H1975, PC9ER, BID007) and Ba/F3 cells harboring clinically relevant EGFR mutants for first (erlotinib), second (afatinib) and third (osimertinib and nazartinib) generation EGFR-TKIs with MTS assay and western blotting. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR.
Result:
Among various mutation types, sensitivities to EGFR-TKI were different. For classic EGFR mutations, exon 19 deletion and L858R, with or without T790M osimertinib showed lower IC50 values and wider therapeutic windows than nazartinib. Afatinib, osimertinib and nazartinib inhibited the phosphorylation of EGFR, AKT, and ERK for human cell lines and Ba/F3 cells harboring these EGFR mutations. For uncommon EGFR mutations, G719S or L861Q, afatinib showed lowest IC50 values. For G719S+T790M or L861Q+T790M, the IC50 values of osimertinib and nazartinib were around 100 nM, 10 to 100 fold higher than those of classic+T790M mutations. On the other hand, osimertinib and nazartinib showed similar efficacies in cells expressing EGFR exon 20 insertions. For C797S mutations, no EGFR-TKIs demonstrated efficacy.
Conclusion:
The present study provides fundamental osimertinib and nazartinib sensitivity/resistance data in cells expressing a range of EGFR mutations, including uncommon EGFR mutations. The findings highlight the diverse mutation selective sensitivity pattern of EGFR-TKIs. These data may help to inform the selection of EGFR-TKIs for non-small cell lung cancer patients harboring EGFR mutations.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-084 - FGF9-FGFR Pathway Induce Neuroendocrine Differentiation in Lung Epithelial Cells (ID 7553)
09:30 - 09:30 | Author(s): J. Hamamoto
- Abstract
Background:
Small cell lung cancer (SCLC), an aggressive and metastatic disease, accounts for about 15% of lung cancer. Neuroendocrine differentiation is essential molecular event in SCLC development. The mechanisms of neuroendocrine differentiation and SCLC development remain elusive. For the improvement of the prognosis of SCLC patients, clarification of the mechanisms of neuroendocrine differentiation is essential.
Method:
For in vitro experiments, a stable cell line with constitutive expression of FGF9 in MLE12 (a mouse lung alveolar type II cell line transformed by SV40 large T antigen) was established by retroviral infections (H69: SCLC cell line, MLE12: mouse lung epithelial cell line transformed by SV40). Using these cell lines, the effect of FGF9 on proliferation, colony formation capacity and downstream signaling was evaluated by MTS assay, softagar colony formation assay and Western blotting, respectively. For in vivo experiments, these cell lines were transplanted into the immunodeficient mice subcutaneously, and the size of tumor was measured. To evaluate the efficacy of FGFR inhibitors for FGF9-driven lung cancers, AZD4547, selective FGFR inhibitor, was orally administered. For pathological characterization of the tumors, immunohistochemicalstry staining was performed. For patients study, 31 SCLC samples were obtained and the expression of FGF9 was evaluated by immunohistochemistry.
Result:
FGF9 is highly expressed in human SCLC samples (80.6%).FGF9 has oncogenic ability in vitro and its effect may be exerted by the activation of MAPK pathway through FGFR1 and FGFR3 in MLE12 cells. Unexpectedly, pathological analysis revealed FGF9-driven tumors exhibited SCLC histology. FGF9 transforms lung alveolar type II cells to SCLC in vitro and in vivo. Selective FGFR inhibitor, AZD4547 suppressed tumor growth of FGF9-driven MLE12 tumors.
Conclusion:
These results suggest that FGF9 has roles of tumor initiation and progression in lung cancer, especially in SCLC. SCLC which highly expresses FGF9 might may be a target of FGFR inhibitors.
