Sensitivity and resistance of oncogenic RAS-driven tumors to dual MEK and ERK inhibition

  • Simple Summary: Mutations in RAS-family genes frequently cause different types of human cancers. Inhibitors of the MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) protein kinases that function downstream of RAS proteins have shown some clinical benefits when used for the treatment of these cancers, but drug resistance frequently emerges. Here we show that combined treatment with MEK and ERK inhibitors blocks the emergence of resistance to either drug alone. However, if cancer cells have already developed resistance to MEK inhibitors or to ERK inhibitors, the combined therapy is frequently ineffective. These findings imply that these inhibitors should be used together for cancer therapy. We also show that drug resistance involves complex patterns of rewiring of cellular kinase signaling networks that do not overlap between each different cancer cell line. Nonetheless, we show that MAP4K4 is required for efficient cell proliferation in several different MEK/ERK inhibitor resistant cancer cell lines, uncovering a potential new therapeutic target. Abstract: Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.
Author:Antonella Catalano, Mojca Adlesic, Thorsten Kaltenbacher, Rhena F. U. Klar, Joachim Albers, Philipp Seidel, Laura P. Brandt, Tomas Hejhal, Philipp Busenhart, Niklas Röhner, Kyra Zodel, Kornelia Fritsch, Peter Johannes WildORCiDGND, Justus Duyster, Ralph Fritsch, Tilman Brummer, Ian Frew
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/04/13
Date of first Publication:2021/04/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/10/19
Tag:ERK inhibitor; MEK inhibitor; drug resistance; metastasis; mouse tumor model; oncogenic RAS; pancreatic ductal adenocarcinoma; undifferentiated pleomorphic sarcoma
Issue:8, art. 1852
Page Number:31
First Page:1
Last Page:31
This research was funded by the Deutsche Forschungsgemeinschaft (DFG) to I.J.F. (BIOSS Excellence Cluster and CRC 850, project B10), to T.B. (CRC 850, project B4) and to R.F. (CRC850, project C09). TB is supported by a DFG funded Heisenberg professorship (BR 3662/5–1).
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0