Emergence of Resistance to MTI-101 Selects for Favorable MET Phenotype in Lung Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA796292 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17551568_1.fastq.gz | Fastqsanger.gz | |||
| SRR17551568_2.fastq.gz | Fastqsanger.gz | |||
| SRR17551569_1.fastq.gz | Fastqsanger.gz | |||
| SRR17551569_2.fastq.gz | Fastqsanger.gz | |||
| SRR17551570_1.fastq.gz | Fastqsanger.gz |
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Project description:MTI-101 is a first-in-class novel cyclic peptide shown to have anti-tumor activity in both multiple myeloma and castrate-resistant prostate in vivo cancer models. These data suggest the potential for a broad spectrum of anti-cancer activity for this class of compounds. To further delineate determinants of sensitivity and resistance that were not dependent on oncogenic drivers, two isogenic drug resistant cell lines were generated with chronic exposure to MTI-101 in a non-small cell lung cancer (NSCLC) PC-9 (EGFR driven) and a small cell lung cancer (SCLC) H446 (PTEN deleted and c-MYC amplified). Using the isogenic cell line systems coupled with RNA-SEQ, the top enriched GSEA hallmark was downregulation of genes that contribute to epithelial to mesenchymal transition (EMT), a finding that was consistent in both acquired MTI-101 selected resistant cell lines. The RNA-SEQ data correlated with predicted changes in the phenotype, including significant decreased invasion in Matrigel and changes of EMT markers (E-Cadherin, Vimentin and Twist) at the protein level. Furthermore, in the EGFR driven PC-9 cell line, selection for resistance towards MTI-101 resulted in collateral sensitivity toward EGFR inhibitors. To determine the stability of the MET phenotype, cells were removed from drug and tested for invasion and drug resistance every month. These data indicated that the mesenchymal to epithelial transition (MET) phenotype and genotype was stable for a minimum of six months. MTI-101 treatment in PC-9 and H446 cells showed synergistic activity with the standard of care agents Erlotinib, Osimertinib, and Cisplatin when used in combination in PC-9 and H446 cells, respectively. Finally, in vivo data indicates that MTI-101 treatment selects for increased E-Cadherin and decreased Vimentin in H446. In addition, treatment with MTI-101 decreased incidence of bone metastasis in the PC-9 in vivo model. Together, these data indicate that MTI-101 treatment could be used as a tool to delay the emergence of metastatic disease for the treatment of lung cancer.
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Project description:Simple Summary MTI-101 is a first-in-class novel cyclic peptide shown to have anti-tumor activity in both multiple myeloma and castrate-resistant prostate in vivo cancer models. These data suggest the potential for a broad spectrum of anti-cancer activity for this class of compounds. To further delineate determinants of sensitivity and resistance that were not dependent on oncogenic drivers, two isogenic drug-resistant cell lines were generated with chronic exposure to MTI-101 in a non-small cell lung cancer (NSCLC) PC-9 (EGFR driven) and a small cell lung cancer (SCLC) H446 (PTEN deleted and c-MYC amplified). Our data indicate that the chronic exposure of MTI-101 selects for a stable mesenchymal-to-epithelial (MET) genotype and phenotype in both PC-9 and H446 lung cancer cell lines. Abstract MTI-101 is a first-in-class cyclic peptide that kills cells via calcium overload in a caspase-independent manner. Understanding biomarkers of response is critical for positioning a novel therapeutic toward clinical development. Isogenic MTI-101-acquired drug-resistant lung cancer cell line systems (PC-9 and H446) coupled with differential RNA-SEQ analysis indicated that downregulated genes were enriched in the hallmark gene set for epithelial-to-mesenchymal transition (EMT) in both MTI-101-acquired resistant cell lines. The RNA-SEQ results were consistent with changes in the phenotype, including a decreased invasion in Matrigel and expression changes in EMT markers (E-cadherin, vimentin and Twist) at the protein level. Furthermore, in the EGFR-driven PC-9 cell line, selection for resistance towards MTI-101 resulted in collateral sensitivity toward EGFR inhibitors. MTI-101 treatment showed synergistic activity with the standard of care agents erlotinib, osimertinib and cisplatin when used in combination in PC-9 and H446 cells, respectively. Finally, in vivo data indicate that MTI-101 treatment selects for increased E-cadherin and decreased vimentin in H446, along with a decreased incident of bone metastasis in the PC-9 in vivo model. Together, these data indicate that chronic MTI-101 treatment can lead to a change in cell state that could potentially be leveraged therapeutically to reduce metastatic disease.
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