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MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.

ABSTRACT: The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca²⁺ flux. Consistent with the acquired resistant genotype, MTI-101 treatment induces a rapid and robust increase in intracellular Ca²⁺ levels in the parental cells; a finding that was attenuated in the acquired drug resistant cell line. Mechanistically, we show that pharmacological inhibition of store operated channels or reduction in the expression of a component of the store operated Ca²⁺ channel, TRPC1 blocks MTI-101 induced cell death. Importantly, MTI-101 is more potent in specimens obtained from relapsed myeloma patients, suggesting that relapse may occur at a cost for increased sensitivity to Ca²⁺ overload mediated cell death. Finally, we demonstrate that MTI-101 is synergistic when combined with bortezomib, using both myeloma cell lines and primary myeloma patient specimens. Together, these data continue to support the development of this novel class of compounds for the treatment of relapsed myeloma.

SUBMITTER: Emmons MF

PROVIDER: S-EPMC5457439 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.

Emmons Michael F MF Anreddy Nagaraju N Cuevas Javier J Steinberger Kayla K Yang Shengyu S McLaughlin Mark M Silva Ariosto A Hazlehurst Lori A LA

Scientific reports 20170602 1

The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca<sup>2+</sup> flux. Consistent with the acquired resistant genotype, MTI- ...[more]

PMID: 28578393

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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.

Dataset Information

MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.

Publications

MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.

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