第39回日本呼吸器内視鏡学会総会 招請講演 Ignatius Ou先生
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・serial biopsy
・膜型チロシンキナーゼ群のシェーマ：講演中、本論文のシェーマが繰り返し登場
Peter Blume-Jensen & Tony Hunter, Nature 411, 355-365 (17 May 2001), review article Oncogenic kinase signalling
・ALK rearrangementの発見：
Soda et al, Nature 561-566, 2007
・ALK rearrangementの様々なpartners
EML4, KIF5B, TFG, KCL1 etc.
・J-ALEX study
・signaling pathways engaged by EML4-ALK
・BIM deletion polymorphism
King Pan Ng et al, Nature Medicine 18, 521?528, 2012
Faber AC et al, Cancer Discov. Sep;1(4):352-65. 2011
・Crizotinib resistant mutants accelerated screening
Zhang et al, Chemical Biology & Drug Design, Volume 78, Issue 6, pages 999?1005, December 2011
・various ALK-TKI approved and under development
crizotinib
alectinib
ceritinib
brigatinib
X396
RXDX101
ASP3026
TSR-001
PF06463922 (lorlatinib)
・L1171X 2nd mutation: alectinib resistant, ceritinib sensitive. Lung Cancer, 231-234, 2015
・F1174X 2nd mutation: ceritinib resistant, alectinib sensitice. Lung Cancer, 2015 in press
・G1202R
・SRC activation as resistance to ALK-TKI: Crystal et al, Science 1480-1486, 2014
AZD0530とcrizotinibの併用で発育抑制
・EGFR activation as resistance to ALK-TKI
gefitinib+crizotinibの併用で発育抑制：比較的最近になって文献報告が相次いでいる
・small cell carcioma transformation
Fujita et al, J Thorac Oncol 2016
Miyamoto et al, Jpn J Clin Oncol, 170-173, 2016
Takegawa et al, Ann Oncol, 2016
Cha et al, J Thorac Oncol, 2016
・ROS1 fusion partners
CD74
SLC34A2
SDC4
GOPC
ERZ
TPM3
LRIG3
CCDC6
CLTC
KLELR
・OxONc12-01 study：Goto et al, ASCO 2016, east asia (China, Taipei, Korea and Japan)
crizotinib for ROS1+ NSCLC, mPFS 13.4M(10.3M-NR）, censored case 45.7% on data cut-off
・ROS1 resistant mutation G2032R
Awad et al, N Eng J Med, 2013
Katayama et al, Clin Cancer Res, 164-174, 2014
Drilon et al, Clin Cancer Res, 2351-2358, 2016
・NGFR-TRK A,B,C
MPRIP-NTRK1
CD74-NTRK1: Vaishnavi A, Le AT, Doebele RC.Cancer Discov. Jan;5(1):25-34. 2015
・Entrectinib multikinase inhibitor
Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.
Menichincheri M et al,J Med Chem. Apr 14;59(7):3392-408, 2016
・LURET study：ASCO 2016
RET partner: KIF5B, CCDC6
・EGFR fusion: EGFR-RAD51 rearrangement
EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.: Konduri K et al, Cancer Discov. Jun;6(6):601-11. 2016
・EGFR kinase domain duplication（KDD）.: Gallant et al, Cancer Discov. 416-422, 2014
・Neuregulin fusion (NRG1)
Gou et al, Med Oncol 34, 2014
Nakaoku et al, Clin Cancer Res 3087-3093, 2014
・MET exon 14 skipping mutation, Drilon et al, ASCO 2016
・TCGA: Nature 543-550, 2014
・molecular profiling in Japan, Saito et al, Cancer Sci, 713-720, 2016
・EGFR common mutation + C797S allosteric inhibitors
cetuximab? Jiu et al, Nature 2016 in press
・Nivolumab
CheckMate-057: phase III study of Nivolumab for Sq 2nd line: Borghaei et al, N Engl J Med 2015
・KEYNOTE-010, Herbst et al, Lancet, 1540-1550, 2016
・Spigel et al, ASCO 2016 Abst.#9017: mutation burdenとICIs: cut offは15
EML4-ALK mean TMB 2.8
ROS1 mean TMB 3.9
EGFR mean TMB 4.4-4.6
MET mean TMB 6.2
MET exon 14 skipping TMB 6.8
BRAF V600E TMB 10.3
KRAS TMB 19.2
BRCA1 TMB 13.8
BRCA2 TMB 15.6
・Serial multiplex moleular profiring is the only way going forward.
・Serial biopsy is indispensable.
