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F. Morgillo
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Optimizing targeted therapy in lung cancer (ID 56)
- Event: ELCC 2018
- Type: Poster Discussion session
- Track:
- Presentations: 1
- Moderators:F. Cappuzzo, N. Peled
- Coordinates: 4/12/2018, 16:45 - 17:45, Room W
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51PD - Effect of MEK inhibition on PDL1 and and on cytokinesproduction profilein NSCLC cell lines and in human lymphocites (ID 535)
16:45 - 17:45 | Presenting Author(s): F. Morgillo
- Abstract
Background:
Preclinical models suggest that MAPK pathway is implicated in the immune-resistance of tumors and MEK-inhibition can increase the CD8+ T-cell infiltration and the efficacy of PD-1/PD-L1 blockade.
Methods:
First, we evaluated PD-L1 mRNA expression by Real Time qPCR and its protein production, togheter with MAPK proteins in a panel of non-small cell lung cancer (NSCLC) cell lines. Then, we studied the changes in PD-L1 and major histocompatibility complex class-I (MHC-I) expression and cytokines’ production, after inhibition with selumetinib or stimulation of MAPK signalling by phorbol 12-myristate 13-acetate (PMA). In addition, we explored the effect of MEK inhibition on T-cell function by using Peripheral blood mononuclear cells (PBMC) from healthy volunteers.
Results:
A consistent correlation between PD-L1 mRNA and protein expression across cell lines suggested that expression mainly depends on trascriptional regulation, and it is regulated by MAPK signal, through the bindng of p65 to the PD-L1 promoter. Moreover, MEK inhibition resulted in an increased expression of MHC-I on cancer cells and increased mRNA expression levels of IFN gamma, IL-6, IL-1B, and TNFalpha, all molecules involved in the activation and differentiation of TCD8+ cytotoxic lymphocytes (CTL) subset. In this scenario, we also tested the effect of MEK inhibitor on activated T-lymphocytes from PBMC of healthy volunteers. After five days of treatment, RT-qPCR analysis revealed a significant increase of mRNA expression of some typical CD8+ T cell pro-inflammatory cytokines, like IL-12, TNFalpha and IFNgamma.
Conclusions:
These results further support the idea that MEK inhibitor reduces PD-L1 expression and this allows the establishment of a pro inflammatory microenvironment. On the other side, pheripheral T cells, treated with selumetinib, produce pro inflammatory cytokines typical of CTL subset, that seems more involved in immune response against cancer. In this context, MEK inhibition may represent a potential mechanism to convert otherwise resistant cancers and suggest new potential treatment combination strategies of MEK-inhibitors with anti-PD-L1 antibodies in NSCLC.
Clinical trial identification:
Legal entity responsible for the study:
University of Campania “L. Vanvitelli”
Funding:
Has not received any funding
Disclosure:
All authors have declared no conflicts of interest.
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Poster Display session (Friday) (ID 65)
- Event: ELCC 2018
- Type: Poster Display session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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155P - Antitumoral efficacy of dual blockade of EGFR signaling by osimertinib in combination with selumetinib or cetuximab in activated EGFR human NSCLC tumor models (ID 536)
12:30 - 13:00 | Presenting Author(s): F. Morgillo
- Abstract
Background:
Osimertinib is the gold standard for activated-EGFR-NSCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by the addition of the monoclonal antibody, cetuximab, or the MEK1/2-inhibitor, selumetinib, to osimertinibin EGFR-mutated-NSCLC in vivo models.
Methods:
We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827(E746-A759del/T790M-), H1975(L858R/T790M+) and PC9-T790M (E746-A759del /T790M+) xenografts, in second line after the developing of resistance to osimertinib and in first line, and we explored mechanisms of resistance to these treatments.
Results:
The addition of selumetinib or cetuximab to osimertinib in second line reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50–80%, and a median PFS (mPFS) of first plus second line of therapy of 28 weeks. The early use of combinations in first line increased the RR to 90%, with amPFSnot reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0,005) as compared to osimertinib, that achieved in first line a mPFS of 17–18 weeks. Moreover, on ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found hedgehog pathway activation and we demonstrated that triple combination with a Smo inhibitor plus osimertinib.
Conclusions:
We demonstrated that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated-NSCLC and that Hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments.
Clinical trial identification:
Legal entity responsible for the study:
University of Campania “L. Vanvitelli”
Funding:
AstraZeneca partially supported
Disclosure:
All authors have declared no conflicts of interest.
