·þÎñÈÈÏß
×ðÖØ¿Æѧ ¾´Î·ÖÆ¶È ×·ÇóЧÂÊ ¹Ø°®ÉúÃü
ѧÊõ¶¯Ì¬
2121·Ç·²¹¹½¨LOXO-292ÄÍÒ©Ë«Í»±ä¹¤³Ìϸ°ûÖêÖúÁ¦RETÒÖÖƼÁ¿ª·¢
Ðû²¼Ê±¼ä£º
2021-06-22
RET£¨Rearranged during transfection£©»ùÒòÓÚ1985ÄêÊ×´ÎÔÚÈËTÁÜ°ÍÁöϸ°ûÖз¢Ã÷£¬ÇÒ±»ÅжÏΪһ¸öÔ°©»ùÒò£¬RET»ùÒòλÓÚÈËÀà10ºÅ³£È¾É«Ì峤±Û£¨10q11.2£©£¬±àÂëÒ»ÖÖ±£´æÓÚϸ°ûĤÉϵÄÊÜÌåÀÒ°±Ëἤø£¨RTK£©[1]¡£¡£RETÂÑ°×ÔÚ³ÉÊìÀú³ÌÖУ¬ÂÑ°×Ç°Ìåͨ¹ý²î±ðµÄÑ¡ÔñÐÔ¼ôÇз½Ê½£¬Ö÷ÒªÐγÉÁ½ÖÖÂÑ°×ÑÇÐÍRET-9ºÍRET-51¡£¡£RET¼¤Ã¸±»Éñ¾½ºÖÊϸ°ûϵȪԴµÄÉñı»®ÑøÉú³¤Òò×ÓGDNF¼¤»î£¬GFNFÓëGFRα1Á¬ÏµÐγÉGDNF-GFRα1¸´ºÏÎ´Ë¸´ºÏÎïÔÙÓëRETÁ¬ÏµÐγÉÈý¸´ºÏÌ壬ÒýÆðRETµÄ¶þ¾Û»¯£¬²¢ÒýÆðÀÒ°±Ëá²Ð»ù×ÔÁ×Ëữ£¬´Ó¶ø¼¤»îÏÂÓÎÐźÅͨ·[2]£¬°üÀ¨RAS/MARK¡¢¡¢PI3K/AKT¡¢¡¢PLCγ/PKCµÈÐźÅͨ·£¬½ø¶øÒýÆðϸ°ûµÄÔöÖ³·Ö»¯¡¢¡¢Ç¨áã¡¢¡¢ÔÙÉúºÍÉú³¤µÈ[1]¡£¡£
ͼ1. a) RET¼¤Ã¸½á¹¹;b) RET¼¤Ã¸»î»¯»úÖƼ°ÐźÅͨ·¡£¡£
(ͼƬȪԴÓڲο¼×ÊÁÏ[2])
RET»ùÒòÖ°©»úÖÆ£¬Ö÷ÒªÓлùÒòÈںϡ¢¡¢µãÍ»±ä¡¢¡¢»ùÒòÀ©ÔöºÍȾɫÌåÖØÅŵÈ[3]¡£¡£È¾É«ÌåµÄÖØ×é³£»£»áµ¼ÖÂRET»ùÒòÖÐÖÐÖ¹ÁѺóÓë²î±ðµÄÉÏÓλùÒò±¬·¢Èںϣ¬½ø¶øÐγÉÇý¶¯Ö×Áöϸ°ûÔöÖ³µÄÈںϻùÒò¡£¡£ÔÚ1990ÄêºÍ2012ÄêÏȺóÔÚ¼××´ÏÙÈéÍ·×´°©¡¢¡¢·ÎÏÙ°©ºÍÂýÐÔËèϵ°×Ѫ²¡Öз¢Ã÷ÕâÒ»±äÒì¡£¡£ÆäÖÐÈںϻùÒòÖ÷ÒªÓУºKIF5B-RET£¨×î¶à£©£¬CCDC6-RETºÍNCOA4-RET£»£»RET»ùÒòÔÚNSCLC»¼ÕßÖ÷ÒªÒÔRET»ùÒòÈÚºÏÐÎʽ±¬·¢¸Ä±ä£¬Ñо¿ÏÔʾ·ÇСϸ°û·Î°©ÖÐKIF5B©\RETÈÚºÏÔ¼Õ¼ËùÓÐRETÈÚºÏµÄ 68.3 %£¬Æä´ÎΪCCDC6©\RET (16.8 %)¼°NCOA4©\RET (1.2 %)[4]¡£¡£ËäÈ»RET»ùÒòÔÚNSCLC»¼ÕßÖеķ¢²¡ÂʽöΪ1.4 %-2.5 %£¬¿ÉÊÇÎÒ¹úµÄ»¼Õß»ùÊýºÜÊÇ´ó£¬Òò¶øЯ´øRET»ùÒòÈںϵÄNSCLC»¼Õß²¢²»ÉÙ¼û[5]¡£¡£µãÍ»±ä¶àλÓÚGate keeper²Ð»ù£¬Ö÷ÒªÊÇV804λµã£¨V804M£¬V804L£©£¬»¹°üÀ¨ÈܼÁÇ°ÑØÍ»±äG810λµã£¨G810R£¬G810S£¬G810C£¬G810A£¬G810V£©¡¢¡¢M918TºÍC634λµã£¨C634R£¬C634G£¬C634F£¬C634S£¬C634W£¬C634Y£¬C634K£©Í»±äµÈ[1]¡£¡£
ͼ2. ²î±ð°©Ö¢ÖÐRET»ùÒò¸Ä±äµÄ¸ÅÊö¡£¡£
(ͼƬȪԴÓڲο¼×ÊÁÏ[3])
ͼ3. RET»ùÒòµÄÖ÷ÒªÈںϷ½Ê½ºÍµãÍ»±äλµã¡£¡£
(ͼƬȪԴÓڲο¼×ÊÁÏ[1])
2011ÄêºÍ2013Ä꣬FDAºÍEMA»®·ÖÅú×¼VandetanibºÍCabozantinibÓÃÓÚÖÎÁÆÏ£ÍûµÄÍíÆÚµÄMTC»¼Õߣ¬²¢ÒÑÔÚRETÈÚºÏÑôÐÔNSCLC»¼ÕßÖÐÏÔʾ³ö»îÐÔ[1]¡£¡£µ«ÉÏÊöÒ©ÎïÕûÌå¹ØÓÚRET»ùÒòÈÚºÏÍ»±äµÄ°ÐÏòÌØÒìÐÔ²¢²»Ç¿£¬Æä²»µ«ÒÖÖÆRETÂÑ°×Ðźţ¬Í¬Ê±»áÒÖÖÆVEGFR¡¢¡¢EGFRµÈÆäËûÂÑ°×£¬ÓÐÓÃÐÔÏà¶Ô½Ï²î£¬ÇÒ¸±×÷ÓúͷǰÐÏò¶¾ÐÔÔöÌí¡£¡£2020Äê5ÔÂ9ÈÕ£¬FDA¼ÓËÙÅú×¼ÁËLoxo Oncology¹«Ë¾(ÀñÀ´ÆìÏÂ)selpercatinib(LOXO-292£¬Retevmo)ÉÏÊУ¬ÓÃÓÚÖÎÁƲ¿·ÖRETÈںϻùÒòµÄ·ÇСϸ°û·Î°©³ÉÈË»¼Õߣ¬ºÍÍíÆÚRETÍ»±äÑôÐÔ¼××´ÏÙËèÑù°©(MTC)»¼Õß¼°ÍíÆÚ»òתÒƵÄRETÈÚºÏÑôÐÔ¼××´ÏÙ°©»¼Õß¡£¡£ÕâÊÇFDAÅú×¼µÄÊ׿î¸ßÑ¡ÔñÐÔRET¼¤Ã¸ÒÖÖƼÁ¡£¡£Selpercatinib(LOXO-292)ÊÇ¿Ú·þÓÃÒ©µÄATP¾ºÕùÐÔС·Ö×ÓRET¼¤Ã¸ÒÖÖƼÁ£¬Ëü¾ßÓд©Í¸ÖÐÊàÉñ¾ÏµÍ³(CNS)µÄÄÜÁ¦£¬²¢ÇÒ¿ÉÒÔ°ÐÏò¼¤»îÐÔRETÈںϡ¢¡¢µãÍ»±äºÍijЩ»ñµÃÐÔÄÍÒ©Í»±ä(¶Ô°üÀ¨KIF5B-RETºÍCCDC6-RETÈÚºÏÀàÐÍ£¬ÒÔ¼°RET-V804L/MºÍM918TÄÍÒ©Í»±äÃô¸Ð)[1]¡£¡£2020Äê9ÔÂ5ÈÕ£¬FDAÅú×¼À¶Í¼¹«Ë¾(Blueprint Medicines Corporation)¿ª·¢µÄRETÒÖÖƼÁPralsetinib(BLU-667£¬Gavreto)ÉÏÊУ¬ÓÃÓÚÖÎÁÆRETÈÚºÏÑôÐÔתÒÆÐÔ·ÇСϸ°û·Î°©(NSCLC)³ÉÈË»¼Õß[1]¡£¡£2021Äê3ÔÂ24ÈÕ£¬BLU667(ÆÕÀÌæÄá, ÉÌÆ·Ãû£ºÆÕ¼ª»ª®)»ñµÃÖйú¹ú¼ÒÒ©Æ·¼àÊÓÖÎÀí¾Ö(NMPA)Åú×¼£¬ÓÃÓÚ¼ÈÍù½ÓÊܹýº¬²¬»¯ÁƵÄRET»ùÒòÈÚºÏÑôÐԵľֲ¿ÍíÆÚ»òתÒÆÐÔNSCLC³ÉÈË»¼Õߣ¬³ÉΪº£ÄÚÊ׸öÒ²ÊÇÏÖÔÚΨһ»ñÅúµÄRETÒÖÖƼÁ[1]¡£¡£
²»¹ý£¬ÓÌÈçÆäËû°ÐÏòÒ©Ò»Ñù£¬ÄÍÒ©ÊDz»¿É×èÖ¹µÄ¡£¡£2020Äê1ÔÂ24ÈÕ£¬¡¶J Thorac Oncol¡·±¨µÀÁË2ÀýRETÈںϷÇСϸ°û·Î°©»¼ÕßÔÚʹÓÃLOXO-292ºó·ºÆðÈܼÁÇ°ÑØÍ»±ä(RET G810R/S/C)£¬½ø¶øµ¼ÖÂLOXO-292ÄÍÒ©¡£¡£½á¹¹Ä£×ÓÔ¤²â£¬RETÈܼÁÇ°ÑØÍ»±äG810R/S/C/VÍ»±äÔÚ¿Õ¼äÉÏ×è°ÁËSelpercatinibµÄÁ¬Ïµ£¬ÌåÍâÊÔÑé֤ʵ¿¹RET¶à¼¤Ã¸ÒÖÖƼÁMKIºÍÑ¡ÔñÐÔRET TKIs¾ùʧȥ»îÐÔ£¬Pralsetinib(BLU-667)¶ÔG810SÃô¸Ð[6]¡£¡£2021Äê4ÔÂ10ºÅ£¬Loxo Oncology¹«Ë¾±¨µÀ£¬ÔÚ»¼ÕßÖзºÆðRETÈܼÁÇ°ÑØÍ»±äG810λµãºÍÃÅ¿ØÍ»±äV804λµãµÄË«Í»±ä£¬¼°M918TλµãºÍÈܼÁÇ°ÑØÍ»±äG810λµãµÄË«Í»±ä¡£¡£ÌåÍâʵÑéЧ¹ûÏÔʾ£¬RET±¬·¢Ë«Í»±äºó£¬¶ÔSelpercatinib(LOXO-292)ºÍPralsetinib(BLU-667)ÒÖÖƼÁ²»Ãô¸Ð[7]¡£¡£
ͼ4. Ñ¡ÔñÐÔRETÒÖÖƼÁÄÍÒ©ÐÔµÄÄ£Äâ¡£¡£
(ͼƬȪԴÓڲο¼×ÊÁÏ[6])
Õë¶ÔRET¼¤Ã¸ÒÖÖƼÁÒ©Î￪·¢ºÍÐèÇó£¬2121·Ç·²¹¹½¨Ò»ÏµÁÐBa/F3-RETË«Í»±äµÄ¹¤³Ìϸ°ûÖ꣬ÓÃÓÚÕë¶ÔRET°ÐµãµÄ»¯ºÏÎïɸÐò¼°¶¯ÎïҩЧÆÀ¼Û£¬½Ó´ý¿í´ó¿Í»§×ÉѯÏàÖú¡£¡£
ϸ°ûÖêÁбí
²¿·Öϸ°ûÖêÌåÍâÑéÖ¤Êý¾Ý
²¿·Öϸ°ûÖêÌåÄÚÄ£×ÓÑéÖ¤Êý¾Ý
BLU-667 in Ba/F3-KIF5B-RET Model
BLU-667¡¢¡¢LOXO-292 in Ba/F3-KIF5B-RET-V804M Model
BLU-667¡¢¡¢LOXO-292 in Ba/F3-KIF5B-RET-V804L Model
BLU-667¡¢¡¢LOXO-292 in Ba/F3-KIF5B-RET-G810C Model
BLU-667¡¢¡¢LOXO-292 in Ba/F3-KIF5B-RET-G810R Model
BLU-667¡¢¡¢LOXO-292 in Ba/F3-KIF5B-RET-G810S Model
²¿·ÖCDXÄ£×ÓÑéÖ¤Êý¾Ý
LOXO-292 in LC-2/ad Model
LOXO-292 in TT Model
²Î¿¼ÎÄÏ×¼°Í¼Æ¬ÈªÔ´£º
1. The importance of the RET gene in thyroid cancer and therapeutic implications. Nature, 2021 May,17:296–306.
2. To Bud or not to Bud: The RET perspective in CAKUT. Pediatr Nephrol. 2014 Apr; 29(4): 597–608.
3. RET Aberrations in Diverse Cancers. Clin Cancer Res; 23(8) April 15, 2017,1988-1997.
4. Curigliano G, et al. 2021 ASCO, Poster 9089.
5.Öйú·ÇСϸ°û·Î°© RET »ùÒòÈÚºÏÁÙ´²¼ì²âר¼Ò¹²Ê¶. Öлª²¡ÀíѧÔÓÖ¾, 2021, 50(6): 583-591.
6. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. Journal of Thoracic Oncology Vol. 2020.15 No. 4: 541-549.
7. Pre-clinical characterization of potent and selective next-generation RET inhibitors. Loxo Oncology at Lilly. Presented at: AACR Annual Meeting 2021.
2121·Ç·²¹«ÖÚºÅ
Á¢ÒìÒ©ÎïÆÀ¼Û
ÖпÆÒ½ÂöС³ÌÐò
µç»°£º4006 0551 06£¨¹Ù·½ÈÈÏߣ©
0551—67129201£¨¹«Ë¾×ܲ¿£©
꿅᣼www.precedo.cn
µØµã£ººÏ·ÊÊиßÐÂÇøÏ°ÓÑ·¹ú¼Ò¿µ½¡´óÊý¾Ý¹¤ÒµÔ°A6¶°
Copyright © 2021 2121·Ç·² °æȨËùÓÐ | SEO±êÇ©
ÍøÕ¾½¨É裺ÖÐÆó¶¯Á¦ ºÏ·Ê