Claudia Scholl ^{1, 15}, Stefan Fröhling ^{1, 15}, Ian F. Dunn ^{2, 3, 4, 5, 6}, Anna C. Schinzel ^{3, 4, 5, 6}, David A. Barbie ^{3, 4, 5, 6, 7}, So Young Kim ^{3, 4, 5, 6}, Serena J. Silver ⁶, Pablo Tamayo ⁶, Raymond C. Wadlow ^{7, 8}, Sridhar Ramaswamy ^{6, 7, 8, 9}, Konstanze Döhner ¹⁰, Lars Bullinger ¹⁰, Peter Sandy ¹¹, Jesse S. Boehm ⁶, David E. Root ⁶, Tyler Jacks ^{6, 11, 12}, William C. Hahn ^{1, 3, 4, 5, 6} ,   and D. Gary Gilliland ^{1, 3, 6, 9, 13, 14}

¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
² Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
⁴ Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
⁵ Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
⁶ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
⁷ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
⁸ Center for Cancer Research and Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
⁹ Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
¹⁰ Department of Internal Medicine III, University Hospital of Ulm, 89081 Ulm, Germany
¹¹ David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
¹² Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
¹³ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
¹⁴ Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA

¹⁵ These authors contributed equally to this work

An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with “undruggable” genetic alterations.

Cell, Volume 137, Issue 5, 796-798, 29 May 2009
doi:10.1016/j.cell.2009.05.011

http://www.cell.com/abstract/S0092-8674(09)00568-6

Preview:

"Finding and Drugging the Vulnerabilities of RAS-Dependent Cancers".

Charles L. Sawyers ¹

¹ Howard Hughes Medical Institute, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

Summary:

Kinase inhibitors have ushered in the era of targeted therapy, but their utility to date is primarily limited to cancers bearing oncogenic kinase mutations. Two papers in this issue (Luo et al., 2009; Scholl et al., 2009,Luo et al., 2009; Scholl et al., 2009) could change this landscape by uncovering kinase-specific vulnerabilities in tumors with RAS mutations.

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