Research ArticleCancer

The ERBB network facilitates KRAS-driven lung tumorigenesis

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Science Translational Medicine  20 Jun 2018:
Vol. 10, Issue 446, eaao2565
DOI: 10.1126/scitranslmed.aao2565

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A new role for kinase inhibitors

The KRAS oncogene is frequently mutated in a variety of cancer types, including lung cancer. Lung cancers with KRAS mutations are usually difficult to target, and conventional thinking dictates that these tumors are resistant to receptor tyrosine kinase inhibitors because those act upstream of the constitutively active KRAS protein. However, it appears that receptor tyrosine kinase signaling may have an effect on KRAS-driven lung tumors after all, by amplifying their growth beyond the effects of KRAS alone. Kruspig et al. and Moll et al. independently reached this conclusion and identified approved multi-kinase inhibitors that are effective in the setting of KRAS-mutant lung cancer in multiple mouse models, suggesting that this may be a potential treatment strategy for human patients as well.

Abstract

KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.

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