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Alexander Schramm
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.07 - Identification of AHR as a Novel Regulator of Lung Cancer Metastasis (Now Available) (ID 2331)
15:45 - 17:15 | Author(s): Alexander Schramm
- Abstract
- Presentation
Background
Curative treatment of early stage and locally advanced non-small cell lung cancer (NSCLC) relies on surgery and radiotherapy. Adjuvant or simultaneous platin-based chemotherapy is used for risk reduction in patients with large tumors and/or lymph node metastases. Still a large fraction of curatively treated patients dies from metastatic relapse. A better mechanistic understanding of lung cancer metastasis is expected to guide the development of novel rational interventions from prevention, early detection and treatment.
Method
Using a barcoded shRNA library we performed a functional in vivo screen in an orthotopic NSCLC mouse model to find target genes involved in metastatic processes. Barcoded shRNAs with significantly different representation between primary tumors and metastases were identified by next generation sequencing. Prioritized hits were functionally validated by targeted suppression in NCI-H1975 cells. Mechanistic studies were conducted in several NSCLC models in vivo and in vitro.
Result
We identified AHR, a ligand-activated transcription factor involved in regulation of biological responses to planar aromatic hydrocarbons, as potential modulator of lung cancer metastasis. Suppression of endogenous AHR by shRNA enhanced the migratory and invasive capacity of NSCLC cells in vitro. Importantly, NCI-H1975 with targeted suppression of AHR showed increased metastasis formation in an orthotopic model in vivo. High RNA expression of AHR correlates with lower likelihood of progression and superior overall survival in patients with stage I NSCLC. Mechanistically, AHR impacts matrix remodeling genes (MMP19, MMP24) as well as asparagine synthetase (ASNS), all of which have been implied in metastatic progression.
Conclusion
AHR is a novel metastasis-modulating factor in NSCLC. Its mechanism of action provides rational targets for diagnostic and therapeutic interventions.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-43 - A Novel Patient Derived Synchronous Cell Pair with Different Mutations in an ALK-Rearranged Lung Adenocarcinoma Underlines Tumor Heterogeneity (ID 2162)
09:45 - 18:00 | Author(s): Alexander Schramm
- Abstract
Background
ALK targeted therapy can provide prolonged clinical response rates in ALK-rearranged lung adenocarcinoma (ADC) patients. However, most tumors relapse within a few years of treatment pressure due to a variety of resistance mechanisms, including intratumoral heterogeneity. Understanding these mechanisms is of utmost importance to more precisely tailor future targeted therapies.
Method
We established a novel synchronous ALK-translocated lung ADC cell pair from the malignant pleural effusion (PF240-PE) and the pleural carcinosis (PF240-PC) of a 38-year-old female patient following sequential ALK targeted therapy. Immunohistochemistry and mutational analyses were executed in pleural carcinosis tissue specimens and in the tumor cell lines. SRB assays were performed for viability testings following different generations ALK inhibitor treatment alone and combined with SAHA, a pan-HDAC inhibitor. As positive control for all treatment lines we used PF521, another newly established ALK-rearranged but treatment naïve lung ADC cell line. In vivo tumorigenicity was evaluated by performing subcutaneous xenografts.
Result
We identified two distinct resistance mutations in both tissue specimens: a so far non-characterized E1161K and the already described L1152R. Strikingly, PF240-PC harbored E1161K and PF240-PE carried L1152R. Immunohistochemistry showed changes from epithelial/carcinomatous to mesenchymal/sarcomatous differentiation following resistance acquisition. In vitro testing revealed that both cell lines were significantly different in morphology and sensitivity to different generation ALK inhibitors including crizotinib, alectinib and lorlatinib. However, the novel tyrosine kinase inhibitor entrectinib was effective in both E1161K and L1152R mutant cells. Importantly, combination treatment of crizotinib or alectinib plus pan-HDAC inhibitor SAHA yielded strong synergism. Of note, both novel cell lines were highly tumorigenic in vivo. In vivo treatment response profiles are currently under evaluation.
Conclusion
This is the first evidence of the synchronous establishment of two highly distinct patient-derived ALK translocated lung ADC cell lines carrying different resistant mutations. This concept supports the paramount significance of spatiotemporal intratumoral heterogeneity under targeted therapy. Furthermore, our findings showed that HDAC inhibition could enhance sensitivity of resistant tumor cells to ALK targeted therapy in vitro. Altogether, our findings provide strong evidence for the synchronous emergence of multiple resistance mechanisms and emphasize the importance of multiple site re-biopsies to better identify acquired resistance mechanisms under targeted therapy.
