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V. Gregorc
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-064 - MET-Dependent Activation of STAT3 as Mediator of Resistance to MEK Inhibitors in KRAS-Mutant Lung Cancer (ID 4240)
14:30 - 14:30 | Author(s): V. Gregorc
- Abstract
Background:
Targeting the MAPK pathway by MEK inhibition results in limited activity in patients with KRAS-mutant non-small cell lung cancer (NSCLC). The lack of effectiveness may be associated with activation of other effectors including STAT3, as well as MEK inhibition relief from negative feedback loops. Indeed, in KRAS-mutant colorectal cancer, MEK inhibition decreases the activity of the metalloprotease ADAM17, which normally inhibits MET signaling and STAT3 activation by promoting shedding of MET endogenous antagonist, soluble "decoy" MET. Herein, we explore the MET-dependent activation of STAT3 as a mediator of resistance to MEK inhibitors, and whether MET or STAT3 inhibitors can synergistically increase MEK-inhibitor-induced growth inhibition in KRAS-mutant NSCLC cells in vitro.
Methods:
Cell viability was assessed by MTT (thiazolyl blue) assay after treatment with the allosteric MEK inhibitor, selumetinib, the small-molecule dual inhibitor of the MET and ALK receptor tyrosine kinases, crizotinib, and evodiamine, an alkaloid isolated from the dried, unripe Evodia rutaecarpa (Juss.) Benth fruit, that exerts an anticancer effect by inhibiting STAT3. RNA was isolated from four KRAS cell lines and the STAT3 and MET mRNA expression analysis was performed by TaqMan based qRT-PCR. Western blotting was used to assess the effect of selumetinb on ERK, AKT and STAT3 phosphorylation.
Results:
We first evaluated the efficacy of the MEK inhibitor selumetinib in our KRAS-mutant NSCLC cell line panel using an MTT cell proliferation assay. H460 cells were relatively insensitive to selumetinib. Following 48-hour treatment with selumetinib, ERK1/2 and AKT phosphorylation were suppressed but a rebound activation of STAT3 occurred in H460 cells. We next investigated whether MET expression was related to the feedback activation of STAT3 signaling following MEK inhibitor treatment. We compared gene expression profiles of the H460 cell line before and after treatment with selumetinib. Interestingly, we found significant upregulation of MET and STAT3 mRNA expression after seven days of selumetinib treatment. To further interrogate the relationship between MEK inhibition and MET-mediated STAT3 reactivation, H460 cells were treated with the combination of selumetinib and crizotinib or selumetinib and evodiamine. A 72-hour exposure to both combinations resulted in a clear cell synergism, as measured by the combination index (CI) analysis, with a CI of 0.79 and 0.78 respectively.
Conclusion:
Collectively our results showed that the feedback STAT3 activation induced by MET, mitigates the effect of MEK inhibition, and provides rationale for further assessment of combined MEK and MET or STAT3 inhibition in KRAS-mutant NSCLC.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-063 - Molecular Profiling in Advanced Non-Small-Cell Lung Cancer: Preliminary Data of an Italian Observational Prospective Study (ID 4529)
14:30 - 14:30 | Author(s): V. Gregorc
- Abstract
Background:
Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to patients’ histological and clinical features. Despite the existence of national guidelines, routine care is still heterogeneous. Aim of this observational study was to obtain prospectively a clinical practice picture of molecular testing and therapeutic choices in advanced NSCLC patients.
Methods:
Newly diagnosed metastatic or recurrent NSCLC patients enrolled in 38 Italian centres, from November 2014 to November 2015, have been included in the study. Baseline information were collected about molecular profiling performed and therapies.
Results:
A total of 1787 patients were enrolled (64% males, 36% females; median age 67 years-old; 22% never smokers, 31% current smokers, 47% former smokers; 75% adenocarcinoma, and 73% with PS ECOG 0 or 1). The 73.9% of diagnosis was histological, while 26.1% was cytological. 1382 (77%) patients were tested for one or more molecular analysis during the history of disease, for a total of 3532 molecular tests. Only 405 patients did not receive any molecular test. 32.3% of patients presented a genetic alteration: EGFR mutation was reported in 17.8% of cases (319/1787), ALK translocation in 8.8% (82/926), KRAS mutation in 31.9% (154/482), MET amplifications in 15.8% (10/63), BRAF mutations in 3.7% (9/241), ROS1 translocation in 4% (11/269), HER2 mutation in 3.3% (3/89) of cases and FGFR alteration was found in 3 cases (only 15 tested). Considering patients younger than 45 years, never smokers and females, an EGFR mutation was detected in 25.4%, 43.5% and 30.6%, respectively. While 15.6%, 9.5% and 6.3% were ALK rearranged, respectively. For patients receiving an EGFR tyrosine-kinase inhibitor as first-line treatment, among those whose data are evaluable (79.2%), the median interval from diagnosis to first-line was 35 days. EGFR mutated patients received first-line erlotinib, gefitinib and afatinib in 9.4%, 39.1% and 33.8% of cases, respectively. At time of analysis, ALK-rearranged patients received an ALK inhibitor (crizotinib, alectinib or ceritinib) as first and/or second-line in 71.9% of cases. 29.3% of all patients received a maintenance therapy, mainly with pemetrexed (91.2% of cases).
Conclusion:
Routine molecular assessing is properly performed according to the national guidelines. A selection bias in including only those patients performing molecular tests, may explain the high proportion of patients with a molecular alteration. The low number of patients tested for ALK could be partially related to the impossibility to prescribe Crizotinib in first- line. In more than 70% of cases EGFR mutated patients received gefitinib or afatinib as first-line treatment.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-009 - Plasma and Tissue Inflammatory and Angiogenic Biomarkers to Explore Resistance to EGFR-TKIs and Association with VeriStrat Status (ID 5750)
14:30 - 14:30 | Author(s): V. Gregorc
- Abstract
Background:
VeriStrat is a proteomic test validated to be prognostic and predictive of overall survival (OS) to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR wild type patients[1]. Serum Amyloid A1 (SAA1) and its two truncated forms are responsible for 4 of the 8 peaks overexpressed in Veristrat (VS) Poor classified patients. The aim of the study was to explore if the microenvironment, with its complex network mediated by inflammation and angiogenesis could represent the base of the aggressive disease behavior of VS Poor subjects. Moreover, the activity of the immune escape axis PD-1/PD-L1 was explored.
Methods:
Plasma biomarkers analyses were retrospectively performed on plasma baseline samples of 244 patients enrolled in the PROSE trial[1], while exploratory tissue analysis was performed on 37 available histological specimens. Circulating levels of HGF, VEGF, FGF, Cromogranin A (CgA) and its pro- and anti-angiogenic fragments (fragment 1-373 and 1-76, respectively) were determined by an ELISA assay. PD-L1 expression both on tumor cells and inflammatory elements of the tumor microenvironment, and the tissue expression (T) of HGF and its receptor c-MET were measured by immunohistochemistry.
Results:
CgA, HGF, VEGF, and FGF plasma levels were statistically significantly higher in VS Poor subjects. High plasma HGF levels were associated with lower PFS (3.4 versus 2.0 months, HR 1.67; 95% CI 1.25-2.23; p<0.001) and OS (11.2 versus 6.4 months, HR 1.64; 95% CI 1.12-2.23 p=0.002). High PD-L1- tumor expression was associated with worse PFS (5.9 versus 1.9 months, HR 2.28; 95% C.I. 1.14-4.57; p<0.020) and a trend for lower OS (14.6 versus 6.7 months, HR 1.47; 95% CI 0.85-2.53; p=0.165), but not significantly associated with VS status (p=0.656). At the multivariate analysis, CgA, HGF and VEGF were independently associated with VS Poor status. When clinical variables were also included (histology and PS), multivariate analysis evidenced VEGF as the only independent biomarker associated with the VS Poor classification (p=0.0013). Plasma HGF levels (HR 2.083; 95% C.I. 1.306-3.321; p=0.0021) and tumor PD-L1 expression (HR 2.579; 95% CI 1.036-6.421; p=0.0417) remained independent prognostic biomarkers for shorter PFS.
Conclusion:
Inflammation and angiogenesis appear to be associated with the complex processes at the base of the Veristrat signature. Plasma HGF levels and tumor tissue PD-L1 are prognostic in terms of a worse PFS, but VeriStrat remains the only highly reproducible clinically relevant biomarker associated with OS. [1]V Gregorc et al, The Lancet Oncology, p713, 15(7),2014.
