Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR re...

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Published in:	Journal of experimental & clinical cancer research Vol. 38; no. 1; p. 492
Main Authors:	Napolitano, S, Matrone, N, Muddassir, A L, Martini, G, Sorokin, A, De Falco, V, Giunta, E F, Ciardiello, D, Martinelli, E, Belli, V, Furia, M, Kopetz, S, Morgillo, F, Ciardiello, F, Troiani, T
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 16-12-2019 BioMed Central BMC
Subjects:	Analysis Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - pharmacology B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - genetics Cancer metastasis Cancer therapies Cancer treatment Cell Line, Tumor Cetuximab Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Diphenylamine - administration & dosage Diphenylamine - analogs & derivatives Diphenylamine - pharmacology Drug Resistance, Neoplasm - drug effects Epithelial-Mesenchymal Transition - drug effects ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics Erlotinib Hydrochloride - administration & dosage Erlotinib Hydrochloride - pharmacology Female Gene expression Genes HCT116 Cells Health aspects Humans Immune response Kinases MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - genetics MAP Kinase Signaling System - drug effects MEK inhibitor resistance Metastasis Patients PD-L1 inhibitors Stem cells Sulfonamides - administration & dosage Sulfonamides - pharmacology Treatment Outcome Tumors Xenograft Model Antitumor Assays United States > US Italy Germany PD-L1 inhibitors Colorectal cancer MEK inhibitor resistance
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Summary:	Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1756-9966 0392-9078 1756-9966
DOI:	10.1186/s13046-019-1497-0