An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.
An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.
复制标题
DOI：
10.1038/s43018-022-00351-8
复制
发表时间：
2022-04
期刊：
影响因子：
22.7
通讯作者：
Janne, Pasi A.
中科院分区：
文献类型：
--
作者：
To, Ciric;Beyett, Tyler S.;Jang, Jaebong;Feng, William W.;Bahcall, Magda;Haikala, Heidi M.;Shin, Bo H.;Heppner, David E.;Rana, Jaimin K.;Leeper, Brittaney A.;Soroko, Kara M.;Poitras, Michael J.;Gokhale, Prafulla C.;Kobayashi, Yoshihisa;Wahid, Kamal;Kurppa, Kari J.;Gero, Thomas W.;Cameron, Michael D.;Ogino, Atsuko;Mushajiang, Mierzhati;Xu, Chunxiao;Zhang, Yanxi;Scott, David A.;Eck, Michael J.;Gray, Nathanael S.;Janne, Pasi A.
虽然小分子表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)最初对EGFR突变肺癌患者有效，但不可避免地会产生耐药性。结合EGFR上不同部位的变构EGFR抑制剂被开发出来用于治疗带有EGFR突变的癌症，这些突变介导了对现有的ATP竞争性EGFR TKI的耐药性。在本研究中，我们鉴定和研究了突变的选择性变构EGFR抑制剂JBJ-09-063，它在EGFR TKI敏感和耐药模型中都有效，包括EGFR T790M和C797S。我们进一步发现，与EGFR或其他ERBB家族成员的同源或异源二聚，或EGFRL747S突变可以介导对JBJ-09-063的抗性，但不能介导对ATP竞争性EGFR TKIs的抗性。综上所述，我们的研究强调了JBJ-09-063作为单一药物或联合EGFR TKI治疗EGFR突变肺癌的潜在临床应用价值。变构EGFR抑制剂JBJ-09-063对EGFR酪氨酸激酶抑制剂敏感和耐药形式的EGFR L858R非小细胞肺癌都有效。
Although treatment with small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is initially efficacious for patients with EGFR mutant lung cancer, drug resistance inevitably develops. Allosteric EGFR inhibitors that bind to a different site on EGFR were developed to treat cancers with EGFR mutations that mediate resistance to existing ATP-competitive EGFR TKIs. In the present study, we identify and study JBJ-09-063, a mutant selective allosteric EGFR inhibitor that is effective in both EGFR TKI sensitive and resistant models including those with EGFR T790M and C797S. We further uncover that homo- or heterodimerization with EGFR, or other ERBB family members, or the EGFRL747S mutation can mediate resistance to JBJ-09-063 but not to ATP-competitive EGFR TKIs. Taken together, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs in EGFR mutant lung cancer. The allosteric EGFR inhibitor JBJ-09-063 is effective in both EGFR tyrosine kinase inhibitor sensitive and resistant forms of EGFR L858R non-small cell lung cancer.
登录
查看更多内容
影响因子：
28.2
作者：
Gallant JN;Sheehan JH;Shaver TM;Bailey M;Lipson D;Chandramohan R;Red Brewer M;York SJ;Kris MG;Pietenpol JA;Ladanyi M;Miller VA;Ali SM;Meiler J;Lovly CM
通讯作者：
Lovly CM
DOI：
10.1158/1078-0432.ccr-18-0876
发表时间：
2018-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bahcall M;Awad MM;Sholl LM;Wilson FH;Xu M;Wang S;Palakurthi S;Choi J;Ivanova EV;Leonardi GC;Ulrich BC;Paweletz CP;Kirschmeier PT;Watanabe M;Baba H;Nishino M;Nagy RJ;Lanman RB;Capelletti M;Chambers ES;Redig AJ;VanderLaan PA;Costa DB;Imamura Y;Jänne PA
通讯作者：
Jänne PA
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
158.5
作者：
Jaenne, Pasi A.;Yang, James Chih-Hsin;Ranson, Malcolm
通讯作者：
Ranson, Malcolm
DOI：
10.1158/1078-0432.ccr-14-2789
发表时间：
2015-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ercan D;Choi HG;Yun CH;Capelletti M;Xie T;Eck MJ;Gray NS;Jänne PA
通讯作者：
Jänne PA