Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer.

Abstract

Pancreatic cancer is characterized by a high degree of resistance to chemotherapy. Epidermal growth factor receptor (EGFR) inhibition using the small-molecule inhibitor erlotinib was shown to provide a small survival benefit in a subgroup of patients. To identify kinases whose inhibition acts synergistically with erlotinib, we employed a kinome-wide small-interfering RNA (siRNA)-based loss-of-function screen in the presence of erlotinib. Of 779 tested kinases, we identified several targets whose inhibition acted synergistically lethal with EGFR inhibition by erlotinib, among them the S6 kinase ribosomal protein S6 kinase 2 (RPS6KA2)/ribosomal S6 kinase 3. Activated RPS6KA2 was expressed in approximately 40% of 123 human pancreatic cancer tissues. RPS6KA2 was shown to act downstream of EGFR/RAS/mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated kinase (ERK) signaling and was activated by EGF independently of the presence of KRAS mutations. Knockdown of RPS6KA2 by siRNA led to increased apoptosis only in the presence of erlotinib, whereas RPS6KA2 activation or overexpression rescued from erlotinib- and gemcitabine-induced apoptosis. This effect was at least in part mediated by downstream activation of ribosomal protein S6. Genetic as well as pharmacological inhibition of RPS6KA2 by the inhibitor BI-D1870 acted synergistically with erlotinib. By applying this synergistic lethality screen using a kinome-wide RNA interference-library approach, we identified RPS6KA2 as potential drug target whose inhibition synergistically enhanced the effect of erlotinib on tumor cell survival. This kinase therefore represents a promising drug candidate suitable for the development of novel inhibitors for pancreatic cancer therapy.

• Authors: Nada Milosevic, Benjamin Kühnemuth, Leonie Mühlberg, Stefanie Ripka, Heidi Griesmann, Carolin Lölkes, Malte Buchholz, Daniela Aust, Christian Pilarsky, Sebastian Krug, Thomas Gress, Patrick Michl
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 15 Issue 12 Pg. 1354-62 (Dec 2013) ISSN: 1476-5586 [Electronic] United States
• PMID: 24403857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Quinazolines
• RNA, Small Interfering
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Ribosomal Protein S6 Kinases, 90-kDa
• ribosomal protein S6 kinase, 90kDa, polypeptide 3

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Erlotinib Hydrochloride
• Gene Knockdown Techniques
• Genes, Lethal
• Humans
• MAP Kinase Signaling System
• Mice
• Pancreatic Neoplasms
• Quinazolines (pharmacology)
• RNA, Small Interfering (genetics)
• Ribosomal Protein S6 Kinases, 90-kDa (genetics, metabolism)