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Functional Genomics Study Finds Druggable Target in KRAS-mutant Lung Cancer

February 2, 2017, by Amy E. Blum, M.A.

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Structure of wild-type KRAS4b in the GDP-bound form

Credit: Dhirendra Simanshu, NCI RAS Initiative

Oncogenic KRAS mutations are attractive yet elusive targets in non-small cell lung cancer (NSCLC), the most common cause of cancer death worldwide1. KRAS mutations are genetic drivers in one third of lung adenocarcinomas in The Cancer Genome Atlas (TCGA). However, both the pharmacological inaccessibility of KRAS and the frequency of resistance mechanisms prevent the robust inhibition of KRAS oncogenic signaling2.

Seeking an effective way to combat KRAS-driven lung cancers, researchers in the Cancer Target Discovery and Development (CTD2) Network mapped gene interactions in lung cancer cell lines. Their analysis, published in Nature, identified a vulnerability specific to KRAS­-mutant lung cancers that can be treated with available small molecule inhibitors. If combined with genomics-based diagnostics, this finding has the potential to improve the care of many lung cancer patients.

KRAS-mutant Tumors’ Crutch

To begin their search for targets in KRAS-driven lung cancer, the authors used short interfering RNAs (siRNAs) to reduce the expression of genes in lung cancer cell lines. Then, they selected gene sets that are important for the survival of KRAS-mutant lung cancer cells but not KRAS­-wild-type cells. They discovered that genes related to nuclear transport specifically support KRAS-driven tumors. Within nuclear transport genes, nuclear export receptor XPO1 is a known druggable target.

The study demonstrated that KRAS-mutant cell lines are sensitive to XPO1 inhibitors KPT-185 and KPT-330 (Selinexor), which caused increased death of cells in vitro using cell lines, and in vivo using mouse tumor models. Lung cancer cells without KRAS mutations were not sensitive to the inhibitors.

Nuclear Transport Supports NFκB Signalling

By analyzing gene expression in cells sensitive to XPO1 inhibition, the researchers showed that NFκB signaling is enriched in these tumors, suggesting that XPO1 nuclear export is linked to oncogenic NFκB expression in KRAS-driven lung cancer. Furthermore, the authors observed that XPO1 inhibition caused the accumulation of the protein IκBa in the nucleus, where it acts as a negative regulator of NFκB signaling. This indicates that impaired nuclear transport, resulting in the buildup of IκBa in the nucleus, decreases NFκB gene expression and therefore counteracts a core component of KRAS-driven oncogenesis.

Genomics Facilitates Optimized Treatments and Combinations

To identify potential paths to resistance against XPO1 inhibitors, the researchers profiled KRAS-mutant cell lines that did not respond robustly to XPO1 inhibition. This analysis showed that resistant cell lines were characterized by concurrent alterations in FSTL5, resulting in increased YAP1 protein expression and signaling. Though the authors estimate that 17 percent of KRAS­-mutant lung cancers possess concurrent FSTL5 mutations, the study also revealed that combining XPO1 inhibitors with YAP1 pathway inhibitors thwarts the resistance of these cell lines. This combination may therefore sensitize tumors that would otherwise be resistant to XPO1 inhibition.

The reliance of KRAS-mutant tumors on nuclear transport machinery presents a promising new way to target these common and deadly cancers, and XPO1 inhibitors, in particular, may be effective treatments on their own or in combinations. The authors emphasized that though these drugs are likely not effective against all lung cancers, a genomics-guided approach to diagnosis and care would yield the greatest possible benefit for lung cancer patients.


References:

1 International Agency for Research on Cancer. World cancer report 2014. http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014

2 Kim, J., McMillan, E., Kim, H.S., Venkateswaran, N., Makkar, G. Rodriguez-Canales, J., Villalobos, P., Neggers, J.E., Mendiratta, S., Wei, S., et al. (2016). XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature. 538: 114-117. http://www.nature.com/nature/journal/v511/n7511/full/nature13385.html

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