JP2017531433A - 上皮細胞増殖因子受容体キナーゼドメインにおける変異 - Google Patents
上皮細胞増殖因子受容体キナーゼドメインにおける変異 Download PDFInfo
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Abstract
Description
本発明は、癌診断及び癌治療に関するコンパニオン診断に関する。特に、本発明は、診断及び予後判定、並びに癌治療の有効性の予測に有用である変異の検出に関する。
上皮細胞増殖因子受容体(EGFR)は、HER1又はErbBlとしても公知であり、増殖因子受容体の1型チロシンキナーゼファミリーの一員である。これらの膜結合性タンパク質は、様々なシグナル伝達経路と相互作用する細胞内チロシンキナーゼドメインを有する。リガンド結合時に、このファミリーの受容体は、二量体化を受け、引き続きチロシンキナーゼドメインの自己リン酸化を受ける。自己リン酸化は、Ras/MAPK経路、PI3K経路及びAKT経路を含む、細胞内シグナル伝達経路の事象カスケードの引き金を引く。これらの経路を通じて、HERファミリータンパク質は、細胞の増殖、分化、及び生存を調節する。
一実施態様において、本発明は、2257−2277>GCC、又は変異2257−2262 del、又は変異 2266−2277 delからなるヒトEGFR遺伝子のエキソン19に新たに同定された変異を含む、新規DNA配列である。
定義
この開示の理解を促進するために、本明細書において使用される用語の以下の定義が提供される。
肺癌患者試料における変異の同定
組織試料を、肺癌(NSCLC)患者から入手した。これらの生検試料を、ホルマリン固定しパラフィン包埋した組織(FFPET)として保存した。核酸を、試料から単離し、Illumina MISEQ(商標)ゲノムシークエンサー(Illumina社、サンディエゴ、カリフォルニア州)上での直接シークエンシングに供した。
Claims (14)
- 上皮細胞増殖因子受容体(EGFR)遺伝子に変異を伴う細胞を抱える可能性のある腫瘍を有する患者を同定する方法であって、配列番号1における変異2257−2277>GCC、又は変異2257−2262 del、又は変異2266−2277 delにより特徴付けられる、変異されたEGFR遺伝子の存在について患者の試料を試験することを含み;これにより、該患者の試料中の変異の存在は、該患者が、EGFR阻害剤化合物に対し感受性があることを示す、方法。
- 前記EGFR阻害剤化合物が、セツキシマブ、パニツムマブ、エルロチニブ又はゲフィチニブである、請求項1記載の方法。
- 変異G719A、G719C、K745−A750 del K ins、E746V、E746K、L747S、E749Q、A750P、A755V、S768I、L858P、L858R、E746−R748 del、E746−S752 del V ins、L747− E749 del、L747−A750 del P ins、L747−T751 del、L747−T751 del P ins、L747−P753 del S ins、L747−S752 del、R748−P753 del、T751−I759 del T ins、S752−I759 del、P753− K757 del、M766−A767 del AI ins、S768−V769 del SVA ins、G779S、P848L、G857V、L858R、L861Q、L883S、D896Y、2236_2248>ACCC、2237_2244>CGCCC、2252_2277>AC、2240−2264>CGAAAGA、2239_2240 TT>CC、2264 C>A及びE746−A750 del AP insの1又は複数により特徴付けられる、変異されたEGFR遺伝子の存在について、患者の試料を試験すること;並びに、
もし1又は複数の変異が存在するならば、チロシンキナーゼ阻害剤による治療が成功する見込みがあることを決定すること、
を更に含む、請求項1又は2記載の方法。 - チロシンキナーゼ阻害剤療法に対する癌患者の反応の尤度を決定する方法であって、
(a)患者の試料中の、EGFR遺伝子の変異2257−2277>GCC、又は変異2257−2262 del、又は変異2266−2277 delに関して、患者の試料を試験すること、並びに、もし変異が存在するならば、
(b)患者が、チロシンキナーゼ阻害剤療法に対し反応する見込みがあることを決定すること、
を含む、方法。 - 前記チロシンキナーゼ阻害剤療法が、セツキシマブ、パニツムマブ、エルロチニブ又はゲフィチニブを含む、請求項4記載の方法。
- (a)EGFR遺伝子の変異G719A、G719C、K745−A750 del K ins、E746V、E746K、L747S、E749Q、A750P、A755V、S768I、L858P、L858R、E746−R748 del、E746−S752 del V ins、L747−E749 del、L747−A750 del P ins、L747−T751 del、L747−T751 del P ins、L747−P753 del S ins、L747−S752 del、R748−P753 del、T751−I759 del T ins、S752−I759 del、P753−K757 del、M766−A767 del AI ins、S768−V769 del SVA ins、G779S、P848L、G857V、L858R、L861Q、L883S、D896Y、2236_2248>ACCC、2237_2244>CGCCC、2252_2277>AC、2240−2264>CGAAAGA、2239_2240 TT>CC、2264 C>A及びE746−A750 del AP insの1又は複数について、患者の試料を更に試験する工程;並びに
(b)もし変異のいずれかが存在すると報告されたならば、患者は、チロシンキナーゼ阻害剤療法に対し反応する見込みがあるであろうと決定する工程、
を更に含む、請求項4又は5記載の方法。 - 前記1又は複数の変異が、アレル特異的検出法によるか又はDNAシークエンシングにより検出される、請求項1〜6のいずれか一項記載の方法。
- 上皮細胞増殖因子受容体(EGFR)遺伝子に変異を伴う細胞を収容している可能性のある腫瘍を有する患者に、EGFR阻害剤化合物の有効量を投与することにより、該患者の癌を治療するのに使用するためのEGFR阻害剤化合物であって、ここで患者のEGFR遺伝子は、少なくとも1個の核酸変動を含むEGFR遺伝子の形を含むと決定されており、これはEGFR標的化された治療は、患者において有効であることを示し、ここで核酸変動は、配列番号1における変異2257−2277>GCC又は変異2257−2262 del、又は変異2266−2277 delから選択される、EGFR阻害剤化合物。
- 前記化合物が、セツキシマブ、パニツムマブ、エルロチニブ又はゲフィチニブである、請求項8記載の使用のためのEGFR阻害剤。
- 患者の試料が、変異G719A、G719C、K745−A750 del K ins、E746V、E746K、L747S、E749Q、A750P、A755V、S768I、L858P、L858R、E746−R748 del、E746−S752 del V ins、L747−E749 del、L747−A750 del P ins、L747−T751 del、L747−T751 del P ins、L747−P753 del S ins、L747−S752 del、R748−P753 del、T751−I759 del T ins、S752−I759 del、P753−K757 del、M766−A767 del AI ins、S768−V769 del SVA ins、G779S、P848L、G857V、L858R、L861Q、L883S、D896Y、2236_2248>ACCC、2237_2244>CGCCC、2252_2277>AC、2240−2264>CGAAAGA、2239_2240 TT>CC、2264 C>A及びE746−A750 del AP insの1又は複数により特徴付けられる、変異されたEGFR遺伝子の存在について試験されることを推奨すること;並びに、
もしいずれかの変異が検出されたならば、チロシンキナーゼ阻害剤化合物を患者へ投与すること、
を更に含む、請求項8又は9記載の使用のためのEGFR阻害剤。 - 前記1又は複数の変異が、アレル特異的検出法によるか又はDNAシークエンシングにより検出される、請求項8〜10のいずれかに記載の使用のためのEGFR阻害剤。
- 変異−特異的オリゴヌクレオチドにより、ヒトEGFR遺伝子の変異2257−2277>GCC、又は変異2257−2262 del、又は変異2266−2277 delを検出する方法。
- 前記オリゴヌクレオチドが、増幅プライマー又は検出プローブである、請求項12記載の方法。
- 前記1又は複数の変異が、アレル特異的検出法によるか又はDNAシークエンシングにより検出される、請求項12記載の方法。
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