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G. López-Vivanco
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-034 - PD-L1 Expression Can Be a Prognostic Marker in EGFR Mutant NSCLC Patients Treated with Erlotinib (ID 8933)
09:30 - 09:30 | Author(s): G. López-Vivanco
- Abstract
Background:
INF-gamma secreted by CD8+ lymphocytes upregulates PD-L1 expression in cancer cells. We recently identified STAT3 and YAP1 as compensatory mechanisms of resistance to EGFR tyrosine kinase inhibition in EGFR mutant cells. STAT3 and YAP1 up-regulate CCL5 (Rantes) and CXCL5, respectively, with both chemokines attracting the myeloid-derived suppressor cell. STAT3 stimulates DNMT1 by repressing STAT1 and retinoic acid-inducible gene-I (RIG-I) expression. STAT1 and RIG-I are key mediators in INF-gamma signaling. We assume that alterations in the INF-gamma signaling pathway could be present in EGFR mutant NSCLC.
Method:
Total RNA from 53 EGFR mutant NSCLC patients was reversed transcribed and analyzed by qRT-PCR. STAT3, YAP1, RIG-I, STAT1, PD-L1, DNMT1 and CXCL5 mRNA were examined with specific primers/probes in triplicates. Progression-free survival (PFS) and overall survival (OS) were estimated.
Result:
Fifty-three EGFR mutant NSCLC patients treated with erlotinib were analyzed, 72% were female, 62% never-smoked, 70% had exon 19 deletion and 36% brain metastases. A positive correlation was found between RIG-1 and STAT1 (r=0.42, p=0.003). An anti-correlation trend was noted between STAT3 and PD-L1, YAP1 and PD-L1 and DNMT1 and STAT1. Median PFS was 22, 12.9 and 8.6 months for patients with high, intermediate and low PD-L1 mRNA, respectively (P=0.04). Median PFS was numerically longer for patients with low levels of DNMT1, RIG1 STAT1 and CXCL5, although the differences were not statistically significant. A similar trend was observed for OS.
Conclusion:
PD-L1 mRNA could be a prognostic marker in EGFR mutant NSCLC patients. Down-modulation of PD-L1 indicates alterations in pattern-recognition receptors (PRRs), like RIG-1 or downstream interferon signaling factors. The dysregualtion of the pathway 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 INF-gamma signaling pathway.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-073 - TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC (ID 8956)
09:30 - 09:30 | Author(s): G. López-Vivanco
- Abstract
Background:
Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells.
Method:
We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with first-line EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs.
Result:
High levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p=0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p=0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p=0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing.
Conclusion:
AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy
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PL 02 - Presidential Symposium including Top 3 Abstracts and James Cox Lectureship Award Presentation (ID 585)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:Hisao Asamura, Keunchil Park
- Coordinates: 10/17/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 02.04 - SCAT Ph III Trial: Adjuvant CT Based on BRCA1 Levels in NSCLC N+ Resected Patients. Final Survival Results a Spanish Lung Cancer Group Trial (ID 9523)
08:40 - 08:50 | Author(s): G. López-Vivanco
- Abstract
- Presentation
Background:
Postop platinum-based CT is considered standard of care in resected NSCLC with lymph node involvement. BRCA1 and BRCA2 are important DNA repair factors primarily involved in the repair of double strand DNA breaks. BRCA-1 functions may act as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. BRCA1 defficiency enhances Cis resistance and loss of BRCA1 function is associated to sensitivity to DNA-damaging CT and may also be associated with resistance to spindle poisons.
Method:
SCAT randomized phase III multicenter trial tests individualized optimal CT based on expression of BRCA1. After surgery patients (p) with St II and Iii NCSLC were random 1:3 to control arm (3 cycles Cis-Docetaxel) or to experimental arm with treatment assigned according BRCA1 expression levels (low levels: Cis-Gemcitabine; intermediate levels: Cis-Doc; high levels: Docetaxel alone). Stratification factors: N1 vs N2; age < or > 65 y; non-Squamous vs Squamous (Sq) histology; lobectomy vs pneumonectomy). Planned PORT in N2. Primary end-point OS. Secondary end-points DFS, toxicity profile (CTCAE v 3.0) /compliance, recurrence pattern. Statistical hypothesis: 5y survival rate control group (45%) could be increase 20% in experimental arm.
Result:
From June/2007 to May/2013, a total of 591 p were screened and 500 of them were randomized in the study, 108 in control arm, 392 in experimental arm. In experimental arm 110 p received Cis-Gem, 127 Cis-Doc and 110 Doc alone. There were no significant differences between arm for known prognostic factors: Median age 64 y; 79% males, 21% females; 43% Sq, 49% Adenoca, 8% others; 57% former smokers, 32% current smokers, 11% never smokers; pneumonectomy 26%; N1 58%, N2 48%. Median tumor size 4.4 cm (0.8-15.5 cm). Median mRNA BRCA1 levels 15.78 (0.73-132). Mean BRCA1 levels 6.95 in Adenoca vs 20.29 in Sq (p<0.001). Compliance of CT was better in experimental arm with less dose-reductions and without differences according extent of surgery. CT compliance was lower in patients older 70 y. Median PFS: 38.7 m (control), 32.2 m Cis-Gem, 34.3 m Cis-Doc and 41 m Doc. At 5 years, event-free rate is 54% in control arm and 56% in experimental arm and median OS 73.3 m (control) vs 77.5 m (exp) (p=0.75). In experimental arm: Docetaxel alone 80.2 m, Cis-Doc 80.5 m and Cis-Gem 74 m.
Conclusion:
Higher survival than expected in patients with lymph node involvement. No significant difference in survival achieved with the experimental arm. In case of high levels BRCA CT treatment without cisplatin is not detrimental. (Eudract:2007-000067-15; NCTgov: 00478699)
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