8P - Expression of genes associated with anti-viral response in EGFR mutant non-small cell lung cancer (NSCLC)

Date 07 May 2017
Event ELCC 2017
Session Poster Display Session
Topics Non-Small-Cell Lung Cancer, Locally Advanced
Non-Small-Cell Lung Cancer, Metastatic
Lung and other Thoracic Tumours
Pathology/Molecular Biology
Presenter Niki Karachaliou
Citation Annals of Oncology (2017) 28 (suppl_2): ii1-ii5. 10.1093/annonc/mdx090
Authors N. Karachaliou1, A. Giménez-Capitán2, A. Drozdowskyj3, E. Aldeguer2, M. González Cao4, A.F. Cardona5, G. López-Vivanco6, J.M. Sánchez7, M.D.L.L. Gil4, R. Rosell8
  • 1Medical Oncology, Hospital Sagrado Corazon, 08029 - Barcelona/ES
  • 2Quirón Dexeus University Hospital, PANGAEA ONCOLOGY, 08028 - Barcelona/ES
  • 3Pivotal, SL, 28023 - Madrid/ES
  • 4Medical Oncology, Instituto Oncológico Dr Rosell (IOR), Hospital Universitario Quirón-Dexeus, 08028 - Barcelona/ES
  • 5Medical Oncology, Clinica del Country, Bogota/CO
  • 6Medical Oncology, Hospital de Cruces, 48903 - Barakaldo/ES
  • 7Medical Oncology, Hospital Universitario de La Princesa, 28006 - Madrid/ES
  • 8Medical Oncology And Laboratory Of Molecular Biology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES

Abstract

Background

Up-regulation of endogenous retroviruses induces interferon response ("viral mimicry") and potentiates response to immune checkpoint therapy. Pattern-recognition receptors (PRRs), including retinoic acid-inducible gene-I (RIG-I), could up-regulate interferon pathway activating signal transducers and activators of transcription (STAT1), which ultimately induces CD274 (PD-L1) mRNA expression. We assume that alterations in the interferon pathway could be present in EGFR mutant NSCLC. Activation of STAT3 stimulates DNMT1 repressing PRRs. We recently identified YAP1 as a compensatory mechanism of resistance to gefitinib and osimertinib in EGFR mutant cells. Activation of YAP1 up-regulates CXCL5, a chemokine attracting myeloid-derived suppressor cell.

Methods

Total RNA from 53 EGFR mutant NSCLC patients (pts), was reversed transcribed and analyzed by qRT-PCR. RIG-1, STAT1, CD274, DNMT1 and CXCL5 mRNA were examined with specific primers/probes in triplicates. Progression-free survival (PFS) and overall survival (OS) were estimated.

Results

Fifty-three EGFR mutant NSCLC pts treated with erlotinib were analyzed, 65% were female, 65% never-smoked, 32% had brain metastases, 37% had bone metastases and 68% had exon 19 deletion. A close correlation was found between the RIG-1 and STAT1 mRNA levels (r = 0.42, p = 0.02). An anti-correlation trend was noted between DNMT1 and STAT1. Median PFS was 22 mo, 12.9 mo and 8.6 mo for pts with high, intermediate and low PD-L1 mRNA, respectively (P = 0.04). Median PFS was numerically longer for pts with low levels of DNMT1, RIG1 STAT1 and CXCL5, although the differences were not statistically significant. A similar trend was observed for OS.

Conclusions

CD274 (PD-L1) mRNA could be a prognostic marker in EGFR mutant NSCLC pts. Down-modulation of CD274 indicates alterations in PRRs or downstream interferon signaling factors. The pathway dysregulation is multifactorial, and the role of STAT3 and YAP1 hyperactivation merits further research. DNMT1 overexpression ablates STAT1. Since the cyclin-dependent kinase 4 (CDK4) interacts with DNMT1, therapies with CDK4 inhibitors can directly neutralize the main defects in the interferon "viral mimicry" pathway.

Clinical trial identification

Legal entity responsible for the study

Institut d\'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain Institut Català d\'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain

Funding

Institut d\'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain Institut Català d\'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain

Disclosure

All authors have declared no conflicts of interest.