New lung cancer drug resistance pathways found

By identifying new ways that lung cancer cells evade current treatments, researchers have found potential new targets for anticancer drugs.
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Scientists have identified new targets for future lung cancer therapies that may help prevent recurrence, according to a study published November 19, 2019 in eLife.

Lung cancer is one of the leading causes of cancer deaths. Newer lung cancer treatments, such as erlotinib and gefitinib, have helped improve patient outcomes by inhibiting the kinase activity of mutant forms of the protein EGFR, which allows cancer cells to grow quickly. But the cancer-suppressing effects of these drugs only work in the short term and tumour cells that survive the treatment often become resistant to it, suggesting that other proteins might influence the effect of the drugs in lung cancers.

To identify the proteins that help lung cancer cells survive EGFR-targeted treatments, lead author Hao Zeng, a postdoctoral fellow at Novartis Institutes for BioMedical Research, and his colleagues used the gene-editing CRISPR-Cas9 technology to systematically delete proteins one at a time in lung cancer cells. This allowed them to see which proteins help lung cancer cells escape treatment and which proteins make them more susceptible.

They found that lung cancer cells without a protein called RIC8A were more sensitive to the effects of EGFR-inhibitors and fewer cells developed resistance. Further testing revealed that deleting RIC8A turns down a key cell survival pathway, known as the YAP signalling pathway, in the cancer cells.

Deleting a protein called ARIH2, on the other hand, made cancer cells less sensitive to EGFR-inhibitors and more likely to survive treatment. This happened partly because cells without ARIH2 had more of a protein called METAP2 that increases the production of proteins needed for cancer cells to grow.

The findings from this study provide potential novel drug targets to increase the effectiveness of EGFR inhibitors in EGFR-mutant lung cancers, and also broaden our understanding of why some patients do not respond to the drugs.

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