Activated ALK cooperates with N-Myc via Wnt/β-catenin signaling to induce neuroendocrine prostate cancer

Kenji Unno, Zachary R. Chalmers, Sahithi Pamarthy, Rajita Vatapalli, Yara Rodriguez, Barbara Lysy, Hanlin Mok, Vinay Sagar, Huiying Han, Young A. Yoo, Sheng Yu Ku, Himisha Beltran, Yue Zhao, Sarki A. Abdulkadir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of MYCN. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the pathogenesis of neuroblastoma and other malignancies where it cooperates with N-Myc. We previously identified the first case of ALK F1174C-activating mutation in a patient with de novo NEPC who responded to the ALK inhibitor, alectinib. Here, we show that coactivation of ALK and N-Myc (ALK F1174C/N-Myc) is sufficient to transform mouse prostate basal stem cells into aggressive prostate cancer with neuroendocrine differentiation in a tissue recombination model. A novel gene signature from the ALK F1174C/N-Myc tumors was associated with poor outcome in multiple human prostate cancer datasets. ALK F1174C and ALK F1174C/N-Myc tumors displayed activation of the Wnt/ b-catenin signaling pathway. Chemical and genetic ALK inhibition suppressed Wnt/b-catenin signaling and tumor growth in vitro in NEPC and neuroblastoma cells. ALK inhibition cooperated with Wnt inhibition to suppress NEPC and neuroblastoma proliferation in vitro and tumor growth and metastasis in vivo. These findings point to a role for ALK signaling in NEPC and the potential of cotargeting the ALK and Wnt/b-catenin pathways in ALK-driven tumors. Activated ALK and N-Myc are well known drivers in neuroblastoma development, suggesting potential similarities and opportunities to elucidate mechanisms and therapeutic targets in NEPC and vice versa.

Original languageEnglish (US)
Pages (from-to)2157-2170
Number of pages14
JournalCancer Research
Volume81
Issue number8
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Activated ALK cooperates with N-Myc via Wnt/β-catenin signaling to induce neuroendocrine prostate cancer'. Together they form a unique fingerprint.

Cite this