KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells.

Leiser, Dominic; Medova, Michaela; Mikami, Kei; Nisa Hernandez, Lluis; Keogh-Stroka, Deborah M.; Blaukat, Andree; Bladt, Friedhelm; Aebersold, Daniel; Zimmer, Yitzhak (2015). KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells. Molecular oncology, 9(7), pp. 1434-1446. Elsevier 10.1016/j.molonc.2015.04.001

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The MET receptor tyrosine kinase is often deregulated in human cancers and several MET inhibitors are evaluated in clinical trials. Similarly to EGFR, MET signals through the RAS-RAF-ERK/MAPK pathway which plays key roles in cell proliferation and survival. Mutations of genes encoding for RAS proteins, particularly in KRAS, are commonly found in various tumors and are associated with constitutive activation of the MAPK pathway. It was shown for EGFR, that KRAS mutations render upstream EGFR inhibition ineffective in EGFR-positive colorectal cancers. Currently, there are no clinical studies evaluating MET inhibition impairment due to RAS mutations. To test the impact of RAS mutations on MET targeting, we generated tumor cells responsive to the MET inhibitor EMD1214063 that express KRAS G12V, G12D, G13D and HRAS G12V variants. We demonstrate that these MAPK-activating RAS mutations differentially interfere with MET-mediated biological effects of MET inhibition. We report increased residual ERK1/2 phosphorylation indicating that the downstream pathway remains active in presence of MET inhibition. Consequently, RAS variants counteracted MET inhibition-induced morphological changes as well as anti-proliferative and anchorage-independent growth effects. The effect of RAS mutants was reversed when MET inhibition was combined with MEK inhibitors AZD6244 and UO126. In an in vivo mouse xenograft model, MET-driven tumors harboring mutated RAS displayed resistance to MET inhibition. Taken together, our results demonstrate for the first time in details the role of KRAS and HRAS mutations in resistance to MET inhibition and suggest targeting both MET and MEK as an effective strategy when both oncogenic drivers are expressed.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

UniBE Contributor:

Leiser, Dominic; Medova, Michaela; Mikami, Kei; Nisa Hernandez, Lluis; Keogh-Stroka, Deborah M.; Aebersold, Daniel and Zimmer, Yitzhak

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1878-0261

Publisher:

Elsevier

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

06 Apr 2016 12:49

Last Modified:

11 May 2016 22:23

Publisher DOI:

10.1016/j.molonc.2015.04.001

PubMed ID:

25933688

Uncontrolled Keywords:

MET, Mutations, RAS, Resistance, Small molecule inhibitors

BORIS DOI:

10.7892/boris.75352

URI:

https://boris.unibe.ch/id/eprint/75352

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