Reaction Biology<\/a>, to screen FDA-approved drugs against a wide range of kinases \u2014 including many cancer-causing mutations.<\/p>\nOther studies have profiled kinase inhibitors, but they lacked the size, scope, and especially the focus on mutant variants seen in Gujral\u2019s study.<\/p>\n
Gujral\u2019s team analyzed 92 clinical kinase drugs across 758 kinases, including 349 mutant or kinase gene-fusions spanning a wide range of tumor types.<\/p>\n
Lung, lymphoid, skin, brain and central nervous system cancers contributed the most kinase mutations to the dataset, along with breast, uterus, liver, sarcoma and large intestine tumors.\u00a0<\/p>\n
\u201cThese mutated versions are often what drives cancer, so we tested drugs against 349 of them,\u201d Gujral said. \u201cThat hadn\u2019t been done before.\u201d<\/p>\n
By casting such a wide net, Gujral\u2019s team expanded the range of kinase targets for FDA-approved drugs from 89 to 235. Their comprehensive analysis also captured kinase variants from cancers with limited treatment options.<\/p>\n
Overall, they found that at least one drug could strongly block the vast majority of cancer-driving changes, including 94% of kinase mutations and 97% of gene fusions.<\/p>\n
Testing the findings with experiments<\/p>\n
The systematic analysis tested drugs against kinases in purified \u201ctest-tube\u201d conditions, but Gujral\u2019s team also used the data to conduct several pilot experiments using mice and tumor cell models, focusing on commonly mutated kinases in lung cancer.<\/p>\n
They discovered, for example, that the drug tepotinib, an inhibitor designed to block a growth-promoting kinase called MET in lung cancer, can also block the kinase IRAK1\/4 in a brain cancer called glioblastoma.\u00a0<\/p>\n
And because IRAK1\/4 also plays a crucial role in innate immunity and inflammation by regulating cholesterol balances, tepotinib might also provide a treatment strategy in cardiovascular disease.<\/p>\n
They also discovered new workarounds when drugs lose their effectiveness because cancer adapts and becomes resistant.\u00a0 For example, gilteritinib, a drug designed to treat leukemia by inhibiting FLT3, a kinase involved in the production of new blood cells, can also work on drug-resistant MET mutants in lung cancer.<\/p>\n
And some kinase inhibitors, they found, can be combined in a one-two punch that not only blocks the primary kinase but keeps another kinase from initiating a signaling pathway that would help the cancer become drug-resistant.<\/p>\n
Their experiments showed that drugs targeting a particular kinase may not be effective for all mutated variants of that kinase, rendering a standard treatment useless for some patients, especially those with rare cancers and variants. But another drug designed for something else might do the trick.<\/p>\n
\u201cThe goal of precision oncology is simple: match the mutation to the right drug,\u201d Gujral said. \u201cDeveloping new drugs for rare cancers is incredibly challenging, but if existing drugs already target these mutant variants, then that gives us a powerful head start.\u201d\u00a0<\/p>\n","protected":false},"excerpt":{"rendered":"Casting a wide net To find out what a drug can do beyond what it is designed to…\n","protected":false},"author":2,"featured_media":409058,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6],"tags":[5350,168698,9629,4450,51584,85,46,66972,4145,193323,193324,125],"class_list":{"0":"post-409057","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-technology","8":"tag-brain-cancer","9":"tag-dna-mutation","10":"tag-drug-resistance","11":"tag-glioblastoma","12":"tag-human-biology","13":"tag-il","14":"tag-israel","15":"tag-kinase","16":"tag-lung-cancer","17":"tag-rare-cancers","18":"tag-taran-gujral","19":"tag-technology"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/posts\/409057","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/comments?post=409057"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/posts\/409057\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/media\/409058"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/media?parent=409057"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/categories?post=409057"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/il\/wp-json\/wp\/v2\/tags?post=409057"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}