Emergence of Resistance to MTI-101 Selects for a MET Genotype and Phenotype in EGFR Driven PC-9 and PTEN Deleted H446 Lung Cancer Cell Lines.
Emergence of Resistance to MTI-101 Selects for a MET Genotype and Phenotype in EGFR Driven PC-9 and PTEN Deleted H446 Lung Cancer Cell Lines.
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MTI-101是一种新型环状肽，在多发性骨髓瘤和去势抵抗性前列腺体内肿瘤模型中均具有抗肿瘤活性。这些数据表明，这类化合物具有广泛的抗癌活性。为了进一步描述不依赖于致癌驱动因素的敏感性和耐药性的决定因素，在非小细胞肺癌（NSCLC） PC-9 （EGFR驱动）和小细胞肺癌（SCLC） H446 （PTEN缺失和c-MYC扩增）中，慢性暴露于MTI-101产生了两个等基因耐药细胞系。我们的数据表明，MTI-101的慢性暴露在PC-9和H446肺癌细胞系中都选择了稳定的间质-上皮（MET）基因型和表型。MTI-101是一种一流的环肽，通过钙超载以不依赖半胱天酶的方式杀死细胞。了解反应的生物标志物对于定位一种新的治疗方法走向临床发展至关重要。等基因mti -101获得性耐药肺癌细胞系系统（PC-9和H446）结合差异RNA-SEQ分析表明，在两种mti -101获得性耐药细胞系中，上皮-间质转化（EMT）的标志基因集中富集了下调基因。RNA-SEQ结果与表型的变化一致，包括在蛋白水平上减少对Matrigel的侵袭和EMT标记（E-cadherin， vimentin和Twist）的表达变化。此外，在EGFR驱动的PC-9细胞系中，对MTI-101的抗性选择导致了对EGFR抑制剂的附带敏感性。MTI-101治疗分别在PC-9和H446细胞中与标准护理剂厄洛替尼、奥西替尼和顺铂联合使用时显示出协同作用。最后，体内数据表明，MTI-101治疗在H446中选择了E-cadherin增加和vimentin减少，同时在PC-9体内模型中减少了骨转移的发生率。总之，这些数据表明慢性MTI-101治疗可以导致细胞状态的改变，这可能潜在地利用治疗来减少转移性疾病。
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. 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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