Some Targeted Therapies May Miss the Mark – Cancer Therapy Advisor

Posted: October 13, 2019 at 5:43 pm

Whencoauthors Ann Lin and Christopher Giuliano, then at Stony Brook University in NewYork, saw their lab results, they were worried. We were both undergrads at thetime, said Lin. It was our first CRISPR experiment, and we were like, is thisour fault, or is this real?

Using CRISPR, Lin and Giuliano had knocked out the gene for MELK, a kinase reported to be essential in multiple cancer types, and of particular interest in triple-negative breast cancer. Surprisingly, they found that breast cancer cells grew happily even without MELK. Even more strangely, the cells lacking MELK remained vulnerable to OTS167, a MELK inhbitor.1Their advisor, Jason Sheltzer, PhDwho is a fellow at Cold Spring Harbor Laboratorywasnt inclined to blame the odd results on undergraduate incompetence. They began pursuing the hypothesis that the drug must exert its killing activity through other proteins or through some other mechanism.

Fourclinical trials are currently underway testing OTS167 in human cancers yet thedrugs mechanism of action may be misunderstood. Its a real problem: targetedtherapies for cancer overwhelmingly fail clinical trials, according to a recentanalysis,2 with only some 3% to 4% of candidates earning approvalfrom the US Food and Drug administration (FDA).

Thisstatistic startled the researchers and prompted them to broaden theirinvestigation. They tested 10 cancer drugs that targeted 6 different proteins,looking to confirm the published mechanisms of action. The target proteins wereHDAC6, MAPK14/p38, PAK4, PBK, PIM1, and CASP3/caspase-3.

Mostof the evidence implicating these proteins as essential for cancer growth camefrom RNA-interference (RNAi) screens, in which short RNA molecules designed tosilence the gene successfully impaired cancer cell growth. In each case, asmall-molecule inhibitor targeting the protein exists, with demonstratedcancer-killing ability. They intentionally selected drug-target pairs that hadno published resistance-granting mutations, which would unequivocally validatethe mechanism of action.

Whenthey knocked out the genes with CRISPR, Lin and Giuliano found that in everycase, inactivating the gene did not diminish the cancer cells survival. Upontesting 4 of the original RNAi constructs that had been used to identify theproteins as essential, the constructs still hampered the cells growth evenwhen the targeted gene of interest had been knocked out.

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Some Targeted Therapies May Miss the Mark - Cancer Therapy Advisor

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