RNA Therapeutics Institute; Program in Bioinformatics and Integrative Biology; Department of Pathology; Department of Molecular, Cell and Cancer Biology; Program in Molecular Medicine
Cancer Biology | Cell Biology
Genetic lesions that activate KRAS account for approximately 30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically up-regulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras-expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone deacetylase inhibitor and Fas-activating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles' heel in tumors initiated by oncogenic Kras.
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Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml. Citation: Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3648-3653. doi: 10.1073/pnas.1620861114. Epub 2017 Mar 20. Link to article on publisher's site
Fas, Kras, apoptosis, lung cancer
Mou, Haiwei; Moore, Jill; Malonia, Sunil K.; Li, Yingxiang; Ozata, Deniz M.; Hough, Soren; Song, Chun-Qing; Smith, Jordan L.; Fischer, Andrew H.; Weng, Zhiping; Green, Michael R.; and Xue, Wen, "Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis" (2017). Program in Bioinformatics and Integrative Biology Publications and Presentations. 117.