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Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance

Anmbreen Jamroze1, Xiaozhuo Liu1, Dean G Tang1,2

  • 1Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Cancer Heterogeneity and Plasticity
|October 4, 2024
PubMed

Insights

Cancer cell heterogeneity drives resistance to therapies like TKIs and ARSIs. Treatments can induce cancer cell lineage plasticity, promoting further resistance, particularly in prostate cancer.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Therapeutics

Background:

  • Cancer cells exhibit heterogeneity in epigenetic and transcriptional states, influencing phenotype, function, and drug sensitivity.
  • This heterogeneity contributes to tumor resistance against targeted therapies, including tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs).
  • Therapeutic interventions can induce lineage plasticity, or infidelity, in cancer cells, further exacerbating therapy resistance.

Purpose of the Study:

  • To discuss cancer cell lineage plasticity, focusing on treatment-induced switching to basal/stem-like, mesenchymal, and neural lineages.
  • To use prostate cancer (PCa) as a model to illustrate androgen receptor signaling inhibitor (ARSI)-induced lineage plasticity in castration-resistant PCa (CRPC) development.
  • To explore the influence of the tumor microenvironment (TME) on therapy-induced lineage plasticity and summarize its regulators and mechanisms.

Main Methods:

  • Review and synthesis of current literature on cancer cell heterogeneity and lineage plasticity.
  • Focus on prostate cancer as a case study for ARSI-induced lineage infidelity.
  • Discussion of the role of the tumor microenvironment (TME) and key regulatory mechanisms.

Main Results:

  • Cancer cell heterogeneity is a fundamental challenge in cancer treatment, leading to resistance.
  • Therapies, particularly ARSIs in prostate cancer, can induce a switch in cancer cell lineages, contributing to castration-resistant prostate cancer (CRPC).
  • The tumor microenvironment (TME) plays a significant role in modulating therapy-induced lineage plasticity.

Conclusions:

  • Understanding and targeting the regulators of cancer cell lineage infidelity are crucial for improving therapeutic outcomes.
  • Targeting lineage plasticity offers a potential strategy to overcome treatment resistance and extend the therapeutic window.
  • Further research into the mechanisms driving lineage infidelity can lead to novel therapeutic approaches for enhanced patient survival.
Keywords:
androgen receptorcancer cell heterogeneitycancer stem cellscastration-resistant prostate cancerlineage plasticityprostate cancerstemnesstherapy resistance

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