Related Experiment Video

Updated: Aug 8, 2026

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

AKAP13 regulates GLI1/ULK1 axis and drive tumor resistance to next-generation HER2-targeted therapies

Qing Guo1,2,3,4,5, Xinyu Chen6, Linfeng Wu7,8

  • 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Oncogene
|August 7, 2026
PubMed

Insights

A-kinase anchoring protein 13 (AKAP13) drives resistance to HER2-targeted therapies in breast cancer. Inhibiting AKAP13 with A13 resensitizes tumors, offering a new strategy for overcoming drug resistance in HER2-positive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Next-generation HER2-targeted therapies, including TKIs and ADCs, have improved survival for HER2-positive cancer patients.
  • Mechanisms underlying primary and acquired resistance to these therapies remain incompletely understood.
  • Understanding resistance is crucial for developing more effective treatment strategies.

Purpose of the Study:

  • To investigate the molecular mechanisms of primary and acquired resistance to HER2-targeted therapies.
  • To identify novel therapeutic targets for overcoming resistance in HER2-positive breast cancer.
  • To evaluate the potential of A-kinase anchoring protein 13 (AKAP13) as a therapeutic target.

Main Methods:

  • Differential protein profiling of resistant and sensitive HER2-positive breast cancers from clinical trials.
  • High-throughput screening to identify key molecules involved in resistance.
  • In vitro and in vivo experiments to elucidate the role of AKAP13 and test the efficacy of AKAP13 inhibitor A13.
  • Organoid construction from patient-derived tissues for validation.

Main Results:

  • Prolonged exposure to tucatinib induced enrichment of the autophagy pathway in HER2-positive breast cancer cells.
  • AKAP13 was identified as a critical molecule in both primary and acquired resistance, predicting poor prognosis.
  • Silencing AKAP13 diminished resistance to HER2-targeted therapies.
  • AKAP13 inhibits autophagy by suppressing ULK1 expression via the RhoA/PKA/GLI1 pathway.
  • Synergistic efficacy of tucatinib and A13 was demonstrated in preclinical models.
  • AKAP13 upregulation and A13-mediated reversal of resistance were confirmed in patient-derived organoids.

Conclusions:

  • AKAP13 plays a pivotal role in mediating resistance to novel HER2-targeted therapies in breast cancer.
  • Inhibition of AKAP13 represents a promising therapeutic strategy to overcome drug resistance.
  • The combination of A13 with existing HER2-targeted therapies may improve outcomes for HER2-positive cancer patients.

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