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Imane Chaib
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FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP12.03 - SRC-Homology 2 Domain-Containing Phosphatase 2 (SHP2) in Resected Lung Adenocarcinoma (LUAD) (ID 992)
00:00 - 00:00 | Author(s): Imane Chaib
- Abstract
Introduction
Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts).
Methods
We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2.
Results
Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio= 1.83 and 2.28, respectively. p= 0.03 and p=0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib displaces SHP2 into the nucleus, either RMC-4550 alone, or in combination with erlotinib, restores SHP2 into the cytoplasm membrane, limiting AKT and ERK activation.
Conclusion
High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.
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P61 - Tumor Biology and Systems Biology - Basic and Translational Science - KRAS (ID 199)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P61.01 - Imipramine Blue (IP) plus MET Tyrosine Kinase Inhibitors (TKI) Suppress Lung Adenocarcinoma (LUAD) KRAS Mutation Tumor Growth (ID 1348)
00:00 - 00:00 | Author(s): Imane Chaib
- Abstract
Introduction
KRAS mutations in LUAD co-occur with TP53 mutations and LKB1 non-synonymous mutations (nsm), portending a poor prognosis. MET amplification has not been considered. Previously, we identified OTSSP167 as a PAK1 kinase inhibitor with significant activity in A549 (KRASG12-C and LKB1nsm). OTSSP167 plus auranofin (PKCι) shows high synergism and inhibits tumor growth in mice in the H23 cell line (KRASG12-C, p53mut and LKB1nsm) (Ito et al, Cell Comm and Signaling 2019). In addition, OTSSP167 has a potent MELK inhibition effect. We hypothesize that MET expression could be upregulated in KRAS-mutant cell lines, based on the fact that the putative signaling pathway, MELK-forkhead box M1 (FOXM1)-MET, could be present in KRAS mutant cells. In the current study, we examined the combination of MET TKIs with imipramine blue (FOXM1 inhibitor).
Methods
Quantitative real time PCR of MET and FOXM1 was performed in 4 KRAS-mutant cell lines (A549, H23, H460 and Calu6). LKB1 mRNA was assessed in 32 advanced KRAS-mutant LUAD patients. Cell proliferation assays were performed in A549 and H23, and in the EBC1 (MET amplified lung cancer cell line). Synergy was defined by a combination index (CI) of < 0.75 by Chou-Talalay. Cell lines were treated with IP and MET TKIs (crizotinib, savolitinib and tepotinib).
Results
MET mRNA was elevated in A549 and H23 (which both carry LKB1nsm) but not in H460 and Calu6. FOXM1 mRNA was overexpressed in H23. Synergy (CI<0.75) was seen with IP plus tepotinib in the A549 and H23 cell lines, but not in H460 and Calu6. Synergy was also noted with IP plus crizotinib, but not with savolitinib. The CI of IP plus MET TKIs in the EBC1 cell line (which is only MET amplified) was >1. The median overall survival for KRAS-mutant LUAD patients with low LKB1 was 1.1 months versus 19.4 for those with high LKB1 (p=<0.005).
Conclusion
The bona fide of MET TKIs (tepotinib) plus IP in KRAS cell lines with LKB1 nsm, encourages the determination of clinical benefit of tepotinib plus IP in KRAS mutant LUAD patients. The liaison of MET and LKB1 nsm should be further investigated. LKB1 mRNA expression, together with MET and FOXM1 mRNA expression, warrants assessment in KRAS LUAD patients.
