18P - PD-L1 pathway activation as an escape mechanism of resistance to MEK inhibitor treatment in a human colorectal cancer model

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Cancer Biology
Basic Scientific Principles
Presenter Stefania Napolitano
Citation Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362
Authors S. Napolitano1, B. Valentina1, E. Martinelli1, V. Sforza1, P.P. Vitiello1, F. De Vita1, N. Zanaletti1, P. Vitale1, D. Ciardiello2, F. Morgillo2, F. Ciardiello2, T. Troiani1
  • 1Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80130 - Napoli/IT
  • 2Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT



In patients with metastatic colorectal cancer (mCRC) who receive anti-epidermal growth factor receptor (EGFR) therapies, gene alterations that emerge at relapse converge to activate the RAS-MEK-MAPK pathway. MEK is key downstream effectors of the EGFR pathway that should be inhibited to prevent and or delay the onset of acquired resistance to anti-EGFR treatment.


In order to understand the mechanism underlying MEK resistance, SW48 quadruple RAS/BRAF Wild-Type (WT) colorectal cancer (CRC) cell lines were injected subcutaneously into female nude mice and treated with MEK inhibitor (MEKi). When tumors were resuming growth despite MEKi treatment, mice were sacrificed and tumors were removed, cut in several pieces and used to generate in vitro MEK-resistant cell lines (SW48-MR). To investigate the potential molecular pathways involved in MEK-resistance, mRNAs from SW48 and SW48-MR cells were extracted and assessed for global gene expression changes by microarray analysis.


Among the genes that were upregulated in SW48-MR versus SW48 we have identified several genes involved in the PD-L1 pathway. In particular the PD-L1 gene was up regulated approximately 10-fold in the resistant cells as compared to parental cells. Moreover, genes overexpressed in MEK-resistance tumor were functionally related in pathways involving immune cell activation, inflammation, and antigen processing and presentation. These results demonstrate an enhanced immune-reactive microenvironment in MEK-resistant tumors.


These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with other agents and provide an additional mechanism of therapeutic resistance via modulation of host immune responses.

Clinical trial identification


Legal entity responsible for the study

Second University of Naples




All authors have declared no conflicts of interest.