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Review
. 2025 Sep 4;15(9):1783-1793.
doi: 10.1158/2159-8290.CD-24-1866.

Histologic Transformation in Cancer: The Path for Clinical Translation

Ioannis Vathiotis #  1 , Avisek Banerjee #  2   3 , Utsav Sen  2 , Felix C Saalfeld  4 , Debdatta Halder  2 , Andriani Charpidou  1 , Konstantinos N Syrigos  1 , Hidehito Horinouchi  5 , Ashutosh K Tewari  6 , Mark A Dawson  7   8   9 , Martin Wermke  4   10 , Triparna Sen  2   11
Affiliations
Review

Histologic Transformation in Cancer: The Path for Clinical Translation

Ioannis Vathiotis et al. Cancer Discov. .

Abstract

Lineage plasticity, a critical hallmark of cancer progression, enables tumor cells to evade inhibition of primary oncogenic pathways through histologic transformation. This adaptive process, driven by stemness-associated features and epigenetic reprogramming, poses significant challenges in treatment. Using non-small cell lung cancer and prostate cancer as models, we examine the utility of tissue and liquid biopsies in detecting histologic transformations and tailoring treatments to specific subtypes, which has profound clinical implications, potentially improving outcomes in patients with advanced, therapy-resistant disease. We also discuss emerging therapeutic strategies, including novel molecular targets, and address ongoing clinical challenges in managing treatment-emergent histologic transformation.

Significance: The advent of highly effective molecularly targeted therapies results in increased recognition of treatment-emergent histologic transformation. This review not only summarizes current evidence on diagnosis and management of lineage plasticity but also explores therapeutic strategies under study, outlining a framework for clinical translation and successful drug development.

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Conflict of interest statement

T.S. has grant funding from Jazz Pharmaceuticals and Debiopharm.

A.T. has served as a site-PI on pharma/industry-sponsored clinical trials from Kite Pharma Inc., Lumicell, Inc., Dendron Pharmaceuticals, LLC, Oncovir Inc., Blue Earth Diagnostics Ltd., RhoVac ApS., Bayer HealthCare Pharmecauticals Inc., Janssen Research and Development, LLC; and has served as an unpaid consultant to Roivant Biosciences and advisor to Promaxo. He owns equity in Promaxo.

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