Lineage plasticity in cancer: a shared pathway of therapeutic resistance

ABSTRACT Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of

tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated

with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer — the histological transformation of

adenocarcinomas to aggressive neuroendocrine derivatives — was initially described in lung cancers harbouring an _EGFR_ mutation, and was subsequently reported in multiple other

adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape

from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our

understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on

neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open

questions in the field. KEY POINTS * Lineage plasticity can promote both metastasis and therapy resistance. * Histological transformation occurs in up to 5% of _EGFR_-mutant lung

adenocarcinomas and at least 20% of prostate adenocarcinomas on targeted therapy. * RB1 and p53 deficiency are implicated in — but not sufficient for — neuroendocrine transformation. * AKT

pathway activation and aberrant activity of the MYC and SOX families of transcriptional regulators have been implicated as being effectors of histological transformation. Access through your

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SUBSETS OF CANCER CELLS EXPRESSING CX3CR1 ARE ENDOWED WITH METASTASIS-INITIATING PROPERTIES AND RESISTANCE TO CHEMOTHERAPY Article 08 January 2022 TUMOR CELL PLASTICITY IN TARGETED

THERAPY-INDUCED RESISTANCE: MECHANISMS AND NEW STRATEGIES Article Open access 11 March 2023 THE NEUROENDOCRINE TRANSITION IN PROSTATE CANCER IS DYNAMIC AND DEPENDENT ON ASCL1 Article Open

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National Institutes of Health, including U24CA213274 and R01CA197936 (to C.M.R.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, Thoracic Oncology Service, Memorial

Sloan Kettering Cancer Center, New York, NY, USA Álvaro Quintanal-Villalonga, Joseph M. Chan, Helena A. Yu, Triparna Sen & Charles M. Rudin * Program for Computational and Systems

Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA Joseph M. Chan & Dana Pe’er * Parker Institute for Cancer Immunotherapy, Memorial Sloan

Kettering Cancer Center, New York, NY, USA Joseph M. Chan & Dana Pe’er * Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA Charles L.

Sawyers * Howard Hughes Medical Institute, Chevy Chase, MD, USA Charles L. Sawyers Authors * Álvaro Quintanal-Villalonga View author publications You can also search for this author inPubMed

 Google Scholar * Joseph M. Chan View author publications You can also search for this author inPubMed Google Scholar * Helena A. Yu View author publications You can also search for this

author inPubMed Google Scholar * Dana Pe’er View author publications You can also search for this author inPubMed Google Scholar * Charles L. Sawyers View author publications You can also

search for this author inPubMed Google Scholar * Triparna Sen View author publications You can also search for this author inPubMed Google Scholar * Charles M. Rudin View author publications

You can also search for this author inPubMed Google Scholar CONTRIBUTIONS A.Q.-V. and J.M.C. researched and drafted the article. H.A.Y., D.P., C.L.S., T.S. and C.M.R. supervised the

content. All authors wrote, reviewed and edited the manuscript before submission. CORRESPONDING AUTHORS Correspondence to Triparna Sen or Charles M. Rudin. ETHICS DECLARATIONS COMPETING

INTERESTS H.A.Y. has been a consultant on oncology drug development for Astellas Pharma, Astra Zeneca, Daiichi, Lilly, Novartis and Pfizer, and is an inventor on a patent application for

pulsatile use of erlotinib to treat or prevent metastases. C.L.S. serves on the board of directors of Novartis, is a co-founder of ORIC Pharmaceuticals and is a co-inventor of enzalutamide

and apalutamide. He is a science adviser to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra and PMV. C.M.R. has been a consultant on oncology drug

development for AbbVie, Amgen, Ascentage, Astra Zeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Genentech–Roche, Ipsen, Loxo, Pharmamar and Vavotek. He serves on the scientific

advisory boards of Bridge Medicines and Harpoon Therapeutics. The other authors declare no competing interests. ADDITIONAL INFORMATION PEER REVIEW INFORMATION _Nature Reviews Clinical

Oncology_ thanks T. Graeber, M. Wicha and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. PUBLISHER’S NOTE Springer Nature remains neutral with

regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Quintanal-Villalonga,

Á., Chan, J.M., Yu, H.A. _et al._ Lineage plasticity in cancer: a shared pathway of therapeutic resistance. _Nat Rev Clin Oncol_ 17, 360–371 (2020). https://doi.org/10.1038/s41571-020-0340-z

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