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Jillian Wilhelmina Paulina Bracht
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P2.03 - Biology (Not CME Accredited Session) (ID 952)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.03-14 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant and Squamous Cell Non-Small Cell Lung Cancer (NSCLC) (ID 12342)
16:45 - 18:00 | Author(s): Jillian Wilhelmina Paulina Bracht
- Abstract
Background
To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR, KRAS and Squamous cell carcinoma (SCC) cell lines.
a9ded1e5ce5d75814730bb4caaf49419 Method
Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carry EGFR and KRAS mutations, respectively, and H520 PAK1 amplified squamous NSCLC cells. Cell viability assays and western blotting were applied to evaluate the effect of auranofin (PKCi inhibitor) plus IPA-3 (PAK1 inhibitor). Since IPA-3 is only for laboratory use, we also tested auranofin in combination with OTSSP167 (a MELK inhibitor in phase I trials), which, in our experience, inhibits pPAK1 (Thr423 and Thr212 in the HCC827 cell line).
4c3880bb027f159e801041b1021e88e8 Result
Auranofin plus IPA-3 was highly synergistic (CI less than 0.4) in EGFR mutant (HCC827), KRAS mutant (H23) and SCC with PAK1 amplification (H520 cells). Similar synergism was found with the combination of auranofin plus OTSSP167 in the 3 cell lines (Figure). the combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET and CDCP1. We created EGFR mutant gefitinib and osimertinib resistant cell lines (PC9-GR3, GR4, OR2, OR4). Auranofin plus IPA-3 was highly synergistic in all cell lines.
8eea62084ca7e541d918e823422bd82e Conclusion
These observations suggest that the combination of auranofin with OTSSP167 can be used for treatment of different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification.
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P2.03-15 - Integrin-Linked Kinase (ILK), Protein Tyrosine Phosphatase SHP2 and B lymphoma Mo-MLV Insertion Region 1 Homolog (Bmi-1) in EGFR-Mutant NSCLC (ID 12557)
16:45 - 18:00 | Author(s): Jillian Wilhelmina Paulina Bracht
- Abstract
Background
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of multiple signaling pathways. ILK regulates the expression of Bmi-1, a well-known epithelial mesenchymal transition-inducing transcription factor. SHP2 function is required for MAPK pathway activation, and also plays a role in receptor tyrosine kinase signaling pathways.
a9ded1e5ce5d75814730bb4caaf49419 Method
Clinical data were assessed in accordance with the protocol approved by the institutional review board and de-identified for patient confidentiality. Pretreatment tumor specimens from advanced EGFR-mutant NSCLC patients (pts) were collected from eight sites in Spain, France, Italy and Colombia. mRNA gene expression analysis was performed by TaqMan (qRT-PCR). We examined the mRNA levels of ILK, SHP2 and Bmi-1.
4c3880bb027f159e801041b1021e88e8 Result
With a median follow-up of 26.7 months, median progression-free survival (PFS) was 9.3 (95% CI, 7.6-14.2) and 15.7 months (95%CI, 12.3-30.1) for pts with high and low ILK mRNA, respectively (P=0.0002), (HR for disease progression, 2.4; 95% CI, 1.3-4.5; P=0.002). Median PFS was 11.4 (95% CI, 8.2-14) and 24.1 months (95% CI, 8.2-30.9) for pts with high and low SHP2 mRNA, respectively (P=0.009), (HR, 2.4; 95% CI, 1.2-4.7; P=0.01). Median PFS was 8.2 (95% CI, 4.8-13.1) and 24.1 months (95% CI, 14.2-36.5) for pts with high and low SHP2 mRNA, respectively (P=0.001), (HR, 2.9; 95% CI, 1.4-5.9; P=0.002). Median overall survival (OS) was 17.9 (95% CI, 13.2-33) and 34.4 months (95% CI, 18.5-44.2) for pts with high and low ILK mRNA, respectively (P=0.200), (HR, 1.5; 95% CI, 0.79-3; P=0.200). Median OS was 18.5 (95% CI, 14-33) and 36.7 months (95% CI, 16.7-47.1) for pts with high and low SHP2 mRNA, respectively (P=0.018), (HR, 2.5; 95% CI, 1.1-5.8; P=0.020). Median OS was 17.6 (95% CI, 8.6-39.1) and 36.7 months (95% CI, 19.1-64.1) for pts with high and low Bmi-1 mRNA, respectively (P=0.004), (HR, 2.2; 95% CI, 1.0-5.1; P=0.040).
8eea62084ca7e541d918e823422bd82e Conclusion
The disturbance of RTKs, including ILK-SHP2-Bmi-1 axis, occurs frequently in EGFR mutant NSCLC patients, significantly limiting the PFS and OS. The levels of ILK, SHP2 and Bmi-1 could be predictive for upfront combinatory therapy of EGFR TKI plus a MAPK pathway inhibitor (SHP2 or MEK inhibitors).
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