MTOR promotes basal cell carcinoma growth through atypical PKC

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Rachel Y Chow1, Taylor M Levee1, Gurleen Kaur1

  • 1Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.

Experimental Dermatology
|February 22, 2021
PubMed

Insights

Targeting the MTOR pathway offers a new strategy for advanced basal cell carcinomas (BCCs) resistant to SMO inhibitors. Suppressing MTOR reduces tumor growth by inhibiting aPKC, providing a promising therapeutic avenue for BCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Advanced basal cell carcinomas (BCCs) are driven by the Hedgehog (HH) pathway.
  • Many BCCs exhibit resistance to SMO inhibitors, necessitating alternative therapeutic strategies.
  • Identifying pathways that bypass SMO is crucial for treating advanced or metastatic BCC.

Purpose of the Study:

  • To identify alternative therapeutic targets for advanced basal cell carcinomas (BCCs).
  • To investigate the role of the MTOR pathway in BCC tumor growth.
  • To evaluate the efficacy of MTOR inhibition as a treatment for BCC.

Main Methods:

  • RNA-sequencing analysis of human BCC tumor-normal pairs.
  • Immunostaining of human and mouse BCC samples.
  • Pharmacological inhibition of MTOR activity in BCC cells and a mouse BCC tumor model.

Main Results:

  • An MTOR expression signature was identified in BCC.
  • Pharmacological inhibition of MTOR reduced BCC cell proliferation without affecting HH signaling.
  • Treatment with everolimus reduced tumor growth in a mouse BCC model.
  • MTOR inhibition led to reduced activity of its downstream target, aPKC.

Conclusions:

  • MTOR signaling promotes BCC tumor growth, partly through activation of aPKC.
  • Suppressing MTOR represents a promising therapeutic strategy for advanced or metastatic BCC.
  • Targeting MTOR offers a potential alternative treatment for patients resistant to SMO inhibitors.
Keywords:
Hedgehog signallingSMO antagonistcancer heterogeneitycancer therapydrug resistance

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