Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis.
Genetic lesions that activate KRAS account for ∼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 oncogenicKrasis suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression ofKrasHere, we show that tumor cells can survive knockout of oncogenicKras, indicating the existence ofKras-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 oncogenicKrascells andKrasknockout cells, we identified 603 genes that were specifically up-regulated inKrasknockout cells, including theFasgene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas receptor efficiently induced apoptosis ofKrasknockout cells but not oncogenicKras-expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at theFaspromoter. 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.
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605.
Haiwei
H
Mou
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605.
Jill
J
Moore
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
Sunil K
SK
Malonia
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605.|Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, People's Republic of China.
Yingxiang
Y
Li
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605.
Deniz M
DM
Ozata
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605.
Soren
S
Hough
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605.
Chun-Qing
CQ
Song
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605.
Jordan L
JL
Smith
Department of Pathology, University of Massachusetts Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA 01605.
Andrew
A
Fischer
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605.
Zhiping
Z
Weng
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; michael.green@umassmed.edu wen.xue@umassmed.edu.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01604.
Michael R
0000-0003-3017-3298
MR
Green
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605; michael.green@umassmed.edu wen.xue@umassmed.edu.|Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.|Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
Wen
W
Xue
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015854:Up-Regulation; D019014:fas Receptor / Q000235:genetics*
D000906:Antibodies; C491899:Fas protein, mouse; D019014:fas Receptor; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
Fas; Kras; apoptosis; lung cancer