Proteins Identified Block Growth of KRAS-Mutant Cancers

A team of cancer researchers has defined a novel regulatory pathway in KRAS-driven cancers, which offers a potential therapeutic target for their eradication.

Approximately 20% of all human cancers have mutations in the KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) gene. These KRAS-mutant cancers are among the most difficult to treat due to their resistance to chemotherapy.

Investigators at the University of California San Diego (USA) used microRNA (miRNA) functional screens to identify synthetic lethal interactions in KRAS-mutant cancer cells that showed potential be exploited therapeutically.

MiRNAs are a small noncoding family of 19- to 25-nucleotide RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer.

The investigators reported in the October 1, 2016, online edition of the journal Cancer Research that they identified the microRNA miR-1298 in a screen that distinguished between miRNAs that blocked the growth of colorectal and lung cancer cells with mutated KRAS but failed to block the growth of the same types of cancer with normal KRAS. Using affinity purification technology, they identified the proteins tyrosine kinase FAK (Focal adhesion kinase) and the laminin subunit LAMB3 (Laminin subunit beta-3) as functional targets of miR-1298.

Further experiments showed that silencing of FAK or LAMB3 inhibited the growth of mutant KRAS-driven cancer cells, in the same manner as miR-1298. Expression of LAMB3 but not FAK was upregulated by mutant KRAS. In clinical specimens, elevated LAMB3 expression correlated with poorer survival in lung cancer patients with an oncogenic KRAS gene signature, suggesting that it might be a novel candidate biomarker in this disease setting.

“For decades researchers have tried to directly inhibit KRAS activity, but there are no well-defined binding pockets in the protein that we can target with small-molecule drugs,” said senior author Dr. Tariq Rana, professor of pediatrics at the University of California, San Diego. “Instead of trying to deter KRAS itself, we took the approach of looking for other molecules that, when inhibited, are lethal to cells only when KRAS is also mutated.”

“This clinical finding suggests LAMB3 could be used as a prognostic biomarker, and underscores LAMB3’s potential as a therapeutic target for KRAS-driven cancers,” said Dr. Rana. “What is more, it highlights miRNAs as important tools for probing complex biological processes, identifying new therapeutic targets and developing potential new RNA-based therapeutics.”

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