About 5% of all lung cancers have KRAS gene mutation. Mutant KRAS protein activates various down-stream proteins and signaling pathways like MAPK signaling for cell proliferation. No significant effects were, however, reported in clinical trials using MEK inhibitors to suppress MAPK signaling. It is herein demonstrated that combination treatment with MEK inhibitor and either FGFR1 inhibitor or ERBB3 inhibitor is effective in screening tests using cultured cell lines and resulted in tumor regression in model mice.
Lung cancer is the worst among cancer-related deaths in Japan. About 5% of all lung cancers have been known to have KRAS gene mutation. In normal cells, KRAS protein transmits various cell proliferation signals from cell surface receptors to the nucleus. Mutation of KRAS gene causes production of mutant KRAS protein molecules in an activated state, transmitting cell proliferation signals without cease, and plays significant roles in cancer generation and development.
One of such signaling pathways to be activated by mutant KRAS protein, MAPK signaling, is considered to play important roles for cancer cell survival and proliferation. Nonetheless, no significant effects were detected in the clinical trials using MEK inhibitors that should exert certain effects for the suppression of MAPK signaling. Thus, no effective targeted therapy for the lung cancer with KRAS gene mutation has been available.
In the present study by the team of the researchers of Kanazawa University and the researchers of other institutions, cellular signaling pathways were analyzed after administration of MEK inhibitors. It was found not only that MEK inhibitors suppressed MAPK signaling temporarily but also that the suppression of MAPK signaling induced the mechanism, called feedback mechanism, for maintaining signaling pathways at ordinary levels. In addition, the feedback mechanism was shown to be induced by the activation of cell surface receptors. Depending on the cellular state called epithelial-to-mesenchymal transition, the responsible receptor was identified to be ERBB3 in the epithelial-like KRAS mutant lung cancer but FGFR1 in the mesenchymal-like KRAS mutant lung cancer, either of which induced reactivation of MAPK signaling. In the case of mesenchymal-like KRAS mutant lung cancer, combination treatment with MEK inhibitor and FGFR1 inhibitor was shown to be effective in screening tests using cultured cell lines, and the tumor regression in model mice was demonstrated for the first time.
The findings by the current research team indicate possibilities of new targeted therapy for the lung cancer with KRAS mutation, for which there were no effective therapeutic methods so far. It is expected that new targeted therapy will be developed with combination of MEK inhibitor and either FGFR1 inhibitor or ERBB3 inhibitor depending on the state of epithelial-to-mesenchymal transition.
Title: Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS mutant lung cancer
Journal: Cancer Discovery (2016)
Authors: Hidenori KITAI1, Hiromichi EBI1, Shuta TOMIDA2, Konstantinov V. FLOROS3, Hiroshi KOTANI1, Yuta ADACHI1, Satoshi OIZUMI4, Masaharu NISHIMURA4, Anthony C. FABER3, Seiji YANO1
1Kanazawa University, 2Okayama University, 3Virginia Commonwealth University, USA, 4Hokkaido University
Grants-in-Aid for Cancer Research 26830105 and 21390256, Scientific Research on Innovative Areas "Integrative Research on Cancer Microenvironment Network" (22112010A01), Grant-in-Aid for Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from MEXT, AstraZeneca R&D Grant Award, Research grant for developing innovative cancer chemotherapy, Kobayashi Foundation for Cancer Research, NCI Transition Career Development Award (K22CA175276), American Lung Association Lung Cancer Discovery Award, and the George and Lavinia Blick Research Fund.