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N. Karachaliou
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.05 - EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results (ID 4451)
11:30 - 11:36 | Author(s): N. Karachaliou
- Abstract
- Presentation
Background:
ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.
Methods:
Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.
Results:
In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).
Conclusion:
Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): N. Karachaliou
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.03 - YAP-NOTCH and STAT3 Signaling Rebound as a Compensatory Response to Gefitinib or Osimertinib Treatment in EGFR Mutant Lung Cancer (ID 4144)
11:20 - 11:30 | Author(s): N. Karachaliou
- Abstract
- Presentation
Background:
Preclinical studies provide insights to therapy mechanisms of resistance that are not feasible with clinical studies. We investigated the signaling pathways that could be involved in adaptive resistance to gefitinib and/or osimertinib in EGFR mutant cells.
Methods:
We performed several laboratory methods to examine the signaling pathways involved in EGFR mutations. Signal transduction pathway analysis was designed using the Ingenuity Pathway Analysis (IPA) software (https://www.ingenuity.com/) Figure 1
Results:
Pathways mediating EGFR mutations are: i) ERK1/2 via Ras and MEK1/2 ii) AKT via PI3K and iii) STAT3 via JAK (Figure). By Western blot analysis, phosphorylation of Tyr705 on STAT3 was noted after 2 hours of gefitinib or osimertinib treatment in PC9 and H1975 EGFR mutant cells. Unexpectedly, YAP1 phosphorylation on Tyr357 and Notch activation was detected. Co-targeting STAT3 and Src with gefitinib or osimertinib ablates activation of STAT3 and YAP1-NOTCH3 signaling pathways (Figure). In vitro and in vivo, the combinatory therapy of gefitinib or osimertinib plus TPCA-1 (a dual inhibitor of IKKs and STAT3) plus saracatinib (a SFK inhibitor) leads to significant tumor shrinkage in PC9 and H1975 cells. In tumor samples of 64 EGFR mutant NSCLC patients treated with gefitinib, the median progression free survival (PFS) was significantly shorter in those with high levels of HES1, ALDH1A1, ALDH1A3, Bmi1, AXL, CDCP1, SHP2 and ILK (Figure). However, the mRNA levels of STAT3 and YAP1 stand out in the prediction of shorter PFS with a hazard ratio of 3.02 and 2.57, respectively (P<0.001)
Conclusion:
For the first time ever, we reported gefitinib induced activation of theYAP1-NOTCH signaling pathway, in addition to activation of STAT3, in EGFR mutant cells. Secondly, co-targeting STAT3 and Src, together with EGFR, causes significant tumor growth inhibition, in comparison with gefitinib or osimertinib single therapy.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-020 - The Effect of EGF-Pathway Targeted Immunization (EGF PTI) on STAT3 and Cancer Stem Cells in EGFR Mutant NSCLC Cells (ID 4698)
14:30 - 14:30 | Author(s): N. Karachaliou
- Abstract
Background:
The vast majority of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutant tumors will develop disease progression following successful treatment with an EGFR tyrosine kinase inhibitor (TKI). Resistance to EGFR-TKIs is due to various mechanisms, such as the secondary mutation (T790M) or the activation of alternative pathways (MET, AXL). What has not been fully appreciated is that EGFR blockade induces an imbalance in favor of survival, increases activity of STAT3 and enriches lung CSCs through Notch3-dependent signaling. EGF-PTI was designed to elicit an antibody response against EGF, in order to reduce EGF receptor signaling and limit tumor growth. We have explored whether EGF-PTI alone or in combination with EGFR TKIs may efficiently inhibit STAT3 and target CSCs.
Methods:
EGF PTI was provided by Bioven (Europe) Ltd. Gefitinib, erlotinib and the recently FDA-approved third-generation EGFR TKI, AZD9291 (osimertinib) were purchased from Selleck chemicals. Western blotting was used to assess the effect of the drugs on ERK, AKT and STAT3 phosphorylation and on Notch and PARP cleavage in EGFR (del19) mutant NSCLC PC9 cells and gefitinib-resistant PC9-GR4 cells. PC9-GR4 cells have been established in our lab and harbor the resistant T790M mutation (T790M+). The protein expression of AXL and CSCs markers such as HES1 (downstream effector of Notch) and Bmi1 was also examined.
Results:
Gefitinib, erlotinib or AZD9291 suppressed EGFR, ERK1/2 and AKT phosphorylation in PC9 cells but increased STAT3 phosphorylation on the tyrosine residue 705 in both PC9 and PC9-GR4 cells. EGF-PTI suppressed STAT3, EGFR and ERK1/2 and the combination of each of the three EGFR TKIs with EGF-PTI lead to more potent inhibition of STAT3, EGFR and ERK1/2. The EGF-PTI induced AKT phosphorylation was reversed when EGF PTI was combined with EGFR TKIs. Interestingly, EGF-PTI blocked Notch cleavage and decreased the expression of HES1. The expression of Bmi1 and AXL were also attenuated with EGF PTI and apoptosis was enhanced through the induction of PARP cleavage.
Conclusion:
EGF PTI may reverse mechanisms of resistance to single EGFR inhibition and the combination of EGF PTI with EGFR TKIs efficiently inhibits downstream signaling pathways in T790M+ cells. Based on these results, the design of a proof-of-concept trial with the combination of EGF PTI with gefitinib for the first line treatment of EGFR mutant NSCLC patients is in progress.
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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): N. Karachaliou
- 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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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-008 - SiRe Next Generation Sequencing Panel: Effective Diagnostic Tool for Circulating Free DNA Analysis (ID 5624)
14:30 - 14:30 | Author(s): N. Karachaliou
- Abstract
Background:
Tissue availability is a crucial point in NSCLC. The introduction of Liquid Biopsies allows to determine circulant biomarkers, specifically using free DNA. To simultaneously analyze multiple patients sample at high sensitivity, Next Generation Sequencing (NGS) can be narrowed to target a limited number of actionable genes. Here we prospectically applied a lab-developed narrowed gene panel (SiRe) to produce a DNA library covering 568 actionable mutations in six gene (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα).
Methods:
This daily clinical practice study was performed on cfDNA obtained from Non Small Cell Lung Cancer blood samples (serum and plasma) prospectically collected either prior to treatment administration in patients without tissue availability (n = 46) or after a progressive disease (n = 19) from a first line gefitinib (n = 14) or afatinib (n = 5) therapy.
Results:
SiRe detected an activating EGFR mutation in 4/46 (8.9%) cases and in T790M in 9/19 (47.4%) at the time of tumor progression. Using tissue data as gold standard, the SiRe panel showed a sensibility of 90.5% and specificity of 100%.
Conclusion:
The SiRe panel is an effective tool enabling the implementation of NGS for cfDNA mutational profiling in molecular pathology practice.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-010 - AZD9291 as 1st-Line Therapy for EGFR Mutant NSCLC Patients with Concomitant Pretreatment EGFR T790M Mutation. The AZENT Study (ID 4267)
14:30 - 14:30 | Author(s): N. Karachaliou
- Abstract
Background:
Osimertinib (AZD9291) is a selective and irreversible pyrimidine-based inhibitor of the primary activating and the secondary EGFR mutation, T790M, which is the most common mechanism of acquired resistance to 1st and 2nd-generation EGFR tyrosine-kinase inhibitors (TKIs). Progression-free survival (PFS) with osimertinib was 9.6 and 2.8 months (m) for EGFR mutated (EGFR+) NSCLC patients progressing to prior EGFR TKI therapy with and without EGFR T790M mutation, respectively, indicating that the T790M is a predictive biomarker for osimertinib efficacy. Sixty patients from two expansion cohorts of the same study, received 1st-line osimertinib and obtained a PFS of 19.3m. T790M, arising in cis with the primary activating mutation, confers resistance to EGFR TKIs, even in the absence of drug selection. The coexistence of the pretreatment T790M mutation has been under appreciated, in spite of accumulative evidence that is present in a frequency of 35-60% using different detection methods. In our experience, pretreatment T790M mutation is frequently detected by three specific aspects of the method: tumor microdissection, examination of two separate tumor areas, and the use of a peptic nucleid acid clamp that inhibits wild-type allele amplification. Thus, we designed the first phase IIa study to evaluate the safety and efficacy of osimertinib as 1st-line therapy for patients with metastatic EGFR+ NSCLC and concomitant pretreatment T790M mutation.
Methods:
This is a multicenter, single-arm, open-label, non-controlled phase IIa clinical study in Spain. Eligible patients are aged ≥18 years with metastatic EGFR+ NSCLC and by central testing documented presence of pretreatment T790M mutation. Seventy-three patients will receive continuous treatment with osimertinib 80 mg daily until disease progression, intolerable adverse events, consent withdrawal or noncompliance with the study protocol. The primary endpoint is the objective response rate (ORR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial is designed to detect a ≥70% ORR in this patient population. Secondary objectives include PFS, overall survival, time to treatment failure, duration of response and disease control rate. Additional pre-specified secondary objectives of the study are the longitudinal analysis of EGFR mutations (including the T790M and the C797S mutations) in plasma and serum and the expression analysis of a panel of biomarkers with possible predictive value for osimertinib treatment.
Results:
Not applicable
Conclusion:
Not applicable
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-038 - STAT3 and Src-YAP1 Inhibition Results in Greater Necitumumab Sensitivity in Lung Squamous Cell Carcinoma (ID 4242)
14:30 - 14:30 | Author(s): N. Karachaliou
- Abstract
Background:
The anti-EGFR monoclonal antibody (mAb), necitumumab, has been recently approved in combination with chemotherapy, as 1st-line treatment for advanced lung squamous cell carcinoma (LSCC) patients, but with minimal survival benefit. Evidence continues to accumulate that signal transducer and activator of transcription 3 (STAT3) is a promising molecular target for cancer therapies. STAT3 is activated by tyrosine phosphorylation in response to EGF and interleukin-6 (IL-6). In addition to STAT3, IL-6 activates the Src family kinases, and subsequently YES-associated protein 1 (YAP1). STAT3 and Src-YAP1 activation contributes to EGFR inhibitor resistance and concomitant targeting of EGFR and STAT3-Src may represent an effective treatment strategy for LSCC.
Methods:
RNA was isolated from six LSCC cell lines and the mRNA expression analysis of EGFR, STAT3, Src and YAP1 was performed by TaqMan based qRT-PCR. Cell viability was assessed by MTT (thiazolyl blue) assay after treatment with necitumumab and evodiamine, an alkaloid isolated from the dried, unripe Evodia rutaecarpa (Juss.) Benth fruit that exerts an anticancer effect by inhibiting STAT3 and Src. Western blotting was performed to assess the effect of necitumumab on EGFR downstream signaling pathways.
Results:
We first evaluated the expression of EGFR in our panel of LSCC cell lines. We found that almost all of them homogeneously express high levels of EGFR. We then assessed the effect of necitumumab on EGFR downstream signaling in the SK-MES1 cell line. Treatment of SK-MES1 cells with 25ug/ml of necitumumab for seven days was unable to ablate STAT3, Src or YAP1 mRNA expression. Consistent with this, we found that necitumumab suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation on the critical tyrosine residue 705 in a time and dose-dependent manner. We examined the growth inhibitory effect of the necitumumab and evodiamine combination. We performed an MTT cell proliferation assay on SK-MES1 cells and we used a constant ratio drug combination method to determine synergy, additivity, or antagonism. The combination of necitumumab and evodiamine resulted in a clear synergism in SK-MES1 cells as measured by the combination index (CI) analysis, with a CI of 0.74. Experiments in the rest of our LSCC cell lines are ongoing.
Conclusion:
Herein we have examined the role of STAT3 and Src-YAP1 in the context of treatment with the FDA-approved EGFR mAb, necitumumab. Our data provide initial evidence that co-activation of STAT3 and Src-YAP1 may limit the cellular response to EGFR inhibition in LSCC.
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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-047 - Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer (ID 4168)
14:30 - 14:30 | Author(s): N. Karachaliou
- Abstract
Background:
EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC.
Methods:
We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance.
Results:
Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95%CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95%CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital.
Conclusion:
Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.
