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

Date

10 Oct 2016

Session

Poster display

Presenters

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

Author affiliations

  • 1 Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80130 - Napoli/IT
  • 2 Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
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Background

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.

Methods

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.

Results

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.

Conclusions

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

NA

Legal entity responsible for the study

Second University of Naples

Funding

AIRC

Disclosure

All authors have declared no conflicts of interest.

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