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<p>The pivotal role of mTORC2 in cancer progression and metastasis underscores its potential as drug target. Despite this, selective inhibition of mTORC2 without affecting mTORC1 represents an unmet need in cancer therapy. We aimed to exploit RAS-mSIN1 interaction for selective mTORC2 targeting. We developed an 11-mer peptide (S-016-1034) from the RAS-Binding-Domain of mSIN1. Cell-free Biolayer-Interferometry (BLI) studies, confirmed direct binding of S-016-1034 to Ras, unlike its scrambled counterpart. Confocal microscopy and flow-cytometry studies illustrated peptide’s cell-membrane penetration, through non-endosomal route, Cell-based assays, including immunoprecipitation and in-situ proximity-ligation, illustrated disruption of Ras-mSin1 interaction, achieving selective inhibition of mTORC2 over mTORC1. The specificity of mTORC2 inhibition was further substantiated through transcriptomics, cell-based, small model (<i>C. elegans</i>), and 4T1/Balb/c mouse models of breast cancer. These studies highlight the potential of Ras-binding peptide S-016-1034 in selectively inhibiting mTORC2, whereby further optimization may offer promising strategies to halt cancer cell invasion and metastasis.</p>

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Leveraging RAS-mSIN1 interaction to selectively inhibit mTORC2 employing competitive RAS binding peptide: implications in breast cancer metastasis

  • 期刊论文

  • 发表日期：

    2025年8月23日

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  • Javed Miyan,
  • Narayan Kumar,
  • Moinuddin,
  • Showkat Ahmad Malik,
  • Usmani Mohammed Akif,
  • Rohil Hameed,
  • Riyazuddin Mohammed,
  • Parul Dubey,
  • Jhajan lal,
  • Akhilesh Kumar,
  • Harshita Dubkara,
  • Karthik Ramalingam,
  • Deepali Pandey,
  • Jiaur Rahaman Gayen,
  • Sanjeev Kanojiya,
  • Aamir Nazir,
  • Wahajul Haq,
  • Damodara N. Reddy,
  • Ashish Arora,
  • Ravishankar Ramachandran,
  • Smrati Bhadauria

摘要

The pivotal role of mTORC2 in cancer progression and metastasis underscores its potential as drug target. Despite this, selective inhibition of mTORC2 without affecting mTORC1 represents an unmet need in cancer therapy. We aimed to exploit RAS-mSIN1 interaction for selective mTORC2 targeting. We developed an 11-mer peptide (S-016-1034) from the RAS-Binding-Domain of mSIN1. Cell-free Biolayer-Interferometry (BLI) studies, confirmed direct binding of S-016-1034 to Ras, unlike its scrambled counterpart. Confocal microscopy and flow-cytometry studies illustrated peptide’s cell-membrane penetration, through non-endosomal route, Cell-based assays, including immunoprecipitation and in-situ proximity-ligation, illustrated disruption of Ras-mSin1 interaction, achieving selective inhibition of mTORC2 over mTORC1. The specificity of mTORC2 inhibition was further substantiated through transcriptomics, cell-based, small model (C. elegans), and 4T1/Balb/c mouse models of breast cancer. These studies highlight the potential of Ras-binding peptide S-016-1034 in selectively inhibiting mTORC2, whereby further optimization may offer promising strategies to halt cancer cell invasion and metastasis.