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Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint

Dhivya Sridaran1,2, Surbhi Chouhan1,2, Kiran Mahajan1,2,3

  • 1Department of Surgery, Washington University at St Louis, St Louis, MO, 63110, USA.

Nature Communications
|November 14, 2022
PubMed

Insights

Immune checkpoint blockade (ICB) resistance in solid tumors is linked to Activated CDC42 kinase 1 (ACK1) inhibiting T-cell activation. Targeting ACK1 may overcome resistance and improve ICB therapy for unresponsive cancers.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Solid tumors are often resistant to immune checkpoint blockade (ICB) therapies.
  • This resistance is partly due to impaired effector T-cell function and poor tumor infiltration.
  • The precise mechanisms regulating T-cell activation, particularly the role of C-terminal Src kinase (CSK), are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which the oncogenic tyrosine kinase ACK1 influences T-cell activation and ICB resistance.
  • To investigate the role of ACK1-mediated phosphorylation of CSK in regulating T-cell responses.
  • To evaluate the therapeutic potential of targeting ACK1 in ICB-resistant tumors.

Main Methods:

  • Investigated the interaction between ACK1 and CSK using biochemical assays.
  • Utilized gene-deficient mouse models (Tnk2 knockout) to assess the in vivo impact of ACK1.
  • Analyzed patient samples from castration-resistant prostate cancer (CRPC) treated with ICB.
  • Tested the efficacy of an ACK1 small-molecule inhibitor ((R)-9b) in preclinical models.

Main Results:

  • ACK1 phosphorylates CSK at Tyrosine 18 (pY18), enhancing CSK activity and suppressing T-cell activation.
  • Mice lacking ACK1 (Tnk2 gene deficiency) exhibit spontaneous T-cell activation and resistance to ICB-resistant tumor growth.
  • ACK1/pY18-CSK signaling is reactivated in CRPC patients upon ICB treatment, correlating with ICB insensitivity.
  • (R)-9b, an ACK1 inhibitor, effectively inhibits ICB-resistant tumors, highlighting ACK1's enzymatic role in resistance.

Conclusions:

  • ACK1-mediated phosphorylation of CSK is a key mechanism driving T-cell dysfunction and ICB resistance in solid tumors.
  • Targeting ACK1 represents a promising strategy to enhance the efficacy of ICB therapy in currently unresponsive cancer types.
  • This study provides a rationale for developing ACK1 inhibitors to broaden the application of immunotherapy.

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