Coordinate direct input of both KRAS and IGF1 receptor to activation of PI3 kinase in KRAS-mutant lung cancer.

Abstract

UNLABELLED:

Using a panel of non-small cell lung cancer (NSCLC) lines, we show here that MAP-ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS-mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras-induced NSCLC. PI3K pathway activity is dependent on basal IGF1R activity in KRAS-mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS-mutant, but not wild-type, lung cancer cells, whereas acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS-mutant lung cancer cells.

SIGNIFICANCE:

It has not yet been possible to target RAS proteins directly, so combined targeting of effect or pathways acting downstream of RAS, including RAF/MEK and PI3K/AKT, has been the most favored approach to the treatment of RAS -mutant cancers. This work sheds light on the ability of RASto activate PI3K through direct interaction, indicating that input is also required from a receptor tyrosinekinase, IGF1R in the case of KRAS -mutant lung cancer. This suggests potential novel combination therapeutic strategies for NSCLC.

• Authors: Miriam Molina-Arcas, David C Hancock, Clare Sheridan, Madhu S Kumar, Julian Downward
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 5 Pg. 548-63 (May 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23454899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KRAS protein, human
• Proto-Oncogene Proteins
• Phosphatidylinositol 3-Kinases
• Receptor, IGF Type 1
• Mitogen-Activated Protein Kinase Kinases
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
• Cell Line, Tumor
• Humans
• Lung Neoplasms (genetics, metabolism)
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Receptor, IGF Type 1 (metabolism)
• ras Proteins (genetics)