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P.F. Conte
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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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3PD - Co-targeting PIM1 or Src to overcome the limits of single MET inhibition (ID 333)
16:45 - 17:45 | Author(s): P.F. Conte
- Abstract
Background:
Single MET inhibition has controversial effects in MET addicted tumors. Proviral integration site for Moloney murine leukemia virus-1 (PIM1) is activated upon MET inhibition in MET addicted cells. PIM1 drives the expression of receptor tyrosine kinases (RTKs). SHP2, a non-receptor protein tyrosine phosphatase, is central in RTKs signaling and in Src activation. We have shown that the overexpression of RTKs like AXL and the transmembrane protein CUB domain-containing protein-1 (CDCP1) as well as Src activation, are mechanisms of intrinsic resistance to EGFR inhibition in EGFR mutant lung cancer. We are now testing whether RTKs, SHP2 or CDCP1 expression and activation are driven by PIM1 or Src and cause resistance to MET inhibitors in MET addicted tumors.
Methods:
We studied the inhibitory effect of the class I MET inhibitors tepotinib and savolitinib, the pan-PIM inhibitor AZD1208, and the Src inhibitor dasatinib in five MET addicted cell lines: 2 MET amplified lung cancer cells (EBC1 and H1993), 2 MET exon 14 mutant cells (Hs746T and H596) and a glioma cell line that carries the still not well recognized MET exon 7–8 splicing variant (E98). We assessed the effect of combined MET and PIM or MET and Src inhibition in cell viability and protein immunoblotting.
Results:
All the cell lines were sensitive to single MET inhibition (except H596) and resistant to single AZD1208 or dasatinib. The combination of savolitinib or tepotinib with AZD1208 was synergistic in the EBC1 cell line and slightly synergistic or additive in the H1993, Hs746T and E98 cell lines. The combination of savolitinib or tepotinib with dasatinib was highly synergistic in all four cell lines. The treatment of EBC1 cells with tepotinib monotherapy was not able to inhibit AXL activation while it induced the activation of SHP2 and CDCP1. AXL, CDCP1 and SHP2 expression or activation were downregulated when tepotinib was combined with dasatinib.
Conclusions:
Co-targeting PIM or Src with MET can be more effective than MET inhibition alone in MET addicted cell lines. Overexpression and activation of RTKs, CDCP1 and SHP2 can be mechanisms of resistance to single MET inhibition. The investigation of combinatorial strategies in MET addicted tumors, merits further investigation.
Clinical trial identification:
Legal entity responsible for the study:
IGTP – Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain
Funding:
Fundació Obra Social “La Caixa”
Disclosure:
All authors have declared no conflicts of interest.
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PD-L1 expression and tumor microenvironment in advanced lung cancer (ID 59)
- Event: ELCC 2018
- Type: Proffered Paper session
- Track:
- Presentations: 1
- Moderators:G. Scagliotti, F. Skoulidis
- Coordinates: 4/12/2018, 16:45 - 18:15, Room B
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78O - Immune microenvironment of small cell lung cancer (SCLC): Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumor infiltrating lymphocytes (ID 370)
16:45 - 18:15 | Author(s): P.F. Conte
- Abstract
- Presentation
Background:
SCLC represents one of the most aggressive lung malignancies, characterized by a high growth fraction and early metastatic spread. New therapeutic options are badly needed and immunotherapy might represent a promising approach. Unfortunately, so far, no molecular prognostic markers have been validated for clinical practice and data on immune microenvironment are limited.
Methods:
We have retrospectively analyzed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 (22C3 clone, DAKO) was performed on tumor cells (TCs) and on tumor-infiltrating lymphocytes (TILs): positivity was defined as PD-L1 expression on 1% or more TCs or TILs. Immunohistochemistry for CD8 (C8/144B clone, DAKO) and FOXP3 (236A/E7 clone, ABCAM) was also performed. A semiquantitative score was used and CD8 and FOXP3 TILs categorized as positive versus negative.
Results:
The analysis included 104 patients: 48 surgically resected, 18 patients treated with radical-intent chemo-radiotherapy and 38 metastatic. In overall study population, PD-L1 was expressed in TCs in 25% of cases. The expression of PD-L1 was significantly correlated with stage disease (32% stage I-III; 13% metastatic stage; p:0.034 for TCs and p:0.002 for TILs) and with outcome: median OS 46.8 months (m) (95% CI: 22.6 to 71.0) versus (vs) 10.9 m (95% CI: 6.2 to 15.7; p = 0.047) PD-L1 positive vs negative respectively; the relation with outcome however, was not confirmed in multivariate analysis. CD8-positive TILs and FOXP3-positive TILs were present in 59% and 72% of samples respectively. Neither the presence of CD8+ TILs nor that of FOXP3+ TILs was correlated to stage. The presence of FOXP3-positive TILs was associated with improved prognosis among non-metastatic patients: median OS 52.5 m (95% CI: 21.4 to 83.7) vs 20.5 m (95% CI: 0 to 49.2; p = 0.027) FOXP3-positive vs negative TILs, a relation confirmed in multivariate analysis.
Conclusions:
Expression of PD-L1 is reduced in advanced stage SCLC patients. Further studies are needed to understand if down-regulation of PD-L1 is linked to a more aggressive phenotype. The prognostic role of FOXP3 TILs in stage I-III SCLCs warrants further confirmation in larger series of patients.
Clinical trial identification:
Legal entity responsible for the study:
Istituto Oncologico Veneto (IOV), Padua, Italy
Funding:
Università degli Studi di Padova
Disclosure:
All authors have declared no conflicts of interest.
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