{"id":313,"date":"2014-07-01T08:46:50","date_gmt":"2014-07-01T12:46:50","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=313"},"modified":"2021-07-02T08:52:00","modified_gmt":"2021-07-02T12:52:00","slug":"egfrm-non-small-cell-lung-cancer-new-treatments-in-development","status":"publish","type":"post","link":"http:\/\/blogs.shu.edu\/cancer\/2014\/07\/01\/egfrm-non-small-cell-lung-cancer-new-treatments-in-development\/","title":{"rendered":"EGFRm+ non-small cell lung cancer – new treatments in development"},"content":{"rendered":"

For patients with activating mutations to the EGFR receptor kinase, small molecule specific inhibitors Iressa (gefintinib) or Tarceva (erlotinib) are administered as front-line treatments. \u00a0But, non-small cell lung cancers develop resistance after about one year of treatment via a single recurrent missense mutation (T790M) to the tyrosine kinase. \u00a0This is similar to resistance observed in patients with CML (Chronic Myeloid Leukemia) following treatment Gleevec (imatinib), which is mediated by a mutation to the Bcr-Abl transgene.<\/p>\n

The EGFR is a critically important transmembrane receptor that triggers the ras signaling cascades, including MEK and Akt\/PKB, which results in proliferation, and blocking of differentiation and apoptosis – see diagram<\/a>\u00a0from NEJM.\u00a0 Development of drugs to overcome the T970M mutation is very important.<\/p>\n

\"Cata_f1_0807960_6\"<\/a><\/p>\n

 <\/p>\n

Two such drugs are CO1686 (Clovis Oncology) and AZD9291 (AstraZeneca), which are designed to irreversibly block both the tyrosine kinase receptors of the activated EGFR mutation, and the T970M mutation – EGFRm+\/T970M cancers. \u00a0So, these could then be used in lieu of gefitinib or erlotinib. \u00a0The chemical structures of all 4 compounds are shown, below:<\/p>\n

\"images\"<\/a><\/p>\n

\"Chemical-Structures-of-third-generation-irreversible-EFGR-tyrosine-kinase-inhibitors_AZD9291_CO-1686-\u7b2c\u4e09\u4ee3\u4e0d\u53ef\u9006\u8868\u76ae\u751f\u957f\u56e0\u5b50\u53d7\u4f53\u916a\u6c28\u9178\u6fc0\u9176\u6291\u5236\u5242\u7684\u5316\u5b66\u7ed3\u6784\"<\/a><\/p>\n

In recent data reported at ASCO, CO1686 showed a 58% response rate in patients with the T970M mutation, however, 22% developed hyperglycemia requiring insulin treatment. \u00a0AZD9291 showed a 50% response rate in Phase 1 studies. \u00a0It will be interesting to see whether undesirable side effects also develop with AZD9291 given their different chemical structures.<\/p>\n","protected":false},"excerpt":{"rendered":"

For patients with activating mutations to the EGFR receptor kinase, small molecule specific inhibitors Iressa (gefintinib) or Tarceva (erlotinib) are administered as front-line treatments. \u00a0But, non-small cell lung cancers develop resistance after about one year of treatment via a single recurrent missense mutation (T790M) to the tyrosine kinase. \u00a0This is similar to resistance observed in […]<\/p>\n","protected":false},"author":2252,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[21,24,35,19,4],"tags":[176,175,177,173,174,171,179,178,172],"class_list":["post-313","post","type-post","status-publish","format-standard","hentry","category-growth-receptors","category-mutations","category-off-target-effects","category-receptor-tyrosine-kinase-inhibitors","category-signal-transduction","tag-azd9291","tag-co1686","tag-egfr","tag-erlotinib","tag-gefitinib","tag-iressa","tag-nsclc","tag-t970m","tag-tarceva"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/313","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/users\/2252"}],"replies":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/comments?post=313"}],"version-history":[{"count":4,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/313\/revisions"}],"predecessor-version":[{"id":5014,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/313\/revisions\/5014"}],"wp:attachment":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=313"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=313"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=313"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}