Approximately 20% of human tumors (and up to 40-50% of colorectal) contain mutations in the KRAS. This feature is an important factor when deciding how to treat patients since the presence of mutations in KRAS confers resistance to certain drugs used against tumors with other mutations.
However, despite the high frequency of KRAS, it has mutations in human cancers, currently, there is still no therapy directed toward the mutated KRAS protein. The absence of binding sites on the protein to which targeting molecules has prevented the identification of direct inhibitors of the mutant protein. For this reason, other therapeutic approaches have been proposed, such as the use of synthetic lethality, designed to take advantage of the defects of tumor cells – in this case mutations in KRAS – to induce their elimination.
MicroRNAs are small molecules of RNA that regulate gene expression and participate in biological processes, including cancer. At work, the researchers screened through a library of microRNAs, synthetic lethality interactions that would lead to the death of cells with mutations in KRAS. To do this, they compared the action of a battery of microRNAs on cell survival in two identical colon cancer tumor lines in which the only difference was the presence or absence of mutations in KRAS. Subsequently, they validated those microRNAs that had induced the death of cells with mutations in lung cancer cell lines with different mutations in KRAS.
“For decades researchers have tried to directly inhibit KRAS activity, but there are no well-defined binding sites in the protein that we can target for small molecules,” said Tariq Rana, a professor at the University of California San Diego and director of work. “Instead of trying to stop the gene KRAS take the approach of looking for other molecules that they are inhibited are lethal to cells, only when KRAS mutations present.”
Of the identified microRNAs affecting the survival of cells with mutations in KRAS, the highlight was miR-1298. This microRNA inhibits the expression of different proteins, including FAK and LAMB3. The investigators found that the inactivation of FAK or LAMB had the same lethal effects on cells with mutations in KRAS as an expression of miR-1298. In addition, the addition of the proteins rescued the phenotype caused by miR-1298.
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FAK is a component of the protein complexes involved in the adhesion of certain cells and also acts as a mediator in different signaling pathways relevant for cancer, in addition to participating in angiogenesis. LAMB3 forms part of laminin 332 and also intervenes in the junction between cells. The analysis of both proteins in clinical samples of patients revealed a significant increase in expression LAMB3 in patients with mutations in KRAS. In addition, the team found a correlation between elevated levels of LAMB3 and the poorer survival of patients with lung cancer.
An international study creates an extensive catalog of interactions between mutations present in tumors of cancer patients and drugs used in cancer therapies.
The study points out the role of microRNAs in cancer and identifies two proteins as new molecular targets to treat tumors targeted by mutations in the gene KRAS.
The results of the study point to miR-1298 and LAMB3 and FAK proteins as novel molecular targets for treating mutation-directed cancers in KRAS. In addition, the authors argue that LAMB3 could be used as a biomarker for non-small cell lung cancer. On the other hand, a FAK inhibitor is currently being tested in phase 2 clinical trial in non-small cell lung cancer.
“This clinical finding suggests that LAMB3 could be used as a prognostic biomarker and reveals the potential of LAMB3 as a therapeutic target for KRAS-driven cancers,” Rana says. “What’s more, it highlights the role of microRNAs as important tools for testing complex biological processes, identifying new therapeutic targets and developing new RNA-based therapies.”