Carcinogen-induced preinvasive human squamous lung cancer is characterised by a novel atypical basal cell state and presents opportunities for chemoprevention
- 1University of Cambridge
Abstract
There are no adequate carcinogen-induced models of the earliest stages of human squamous lung cancer (LUSC), limiting the development of effective chemoprevention strategies. We developed a novel human model of early LUSC by exposing differentiated primary human airway cells to a chemical carcinogen known to cause murine LUSC. Carcinogen exposure induced a phenotype recapitulating the earliest stages of human LUSC and associated with the emergence of a novel population of atypical basal cells (ABCs). ABCs express key cancer hallmark markers but without evidence of either common LUSC-associated mutations or an emergent major clonal/subclonal population. We established the clinical relevance of this model by demonstrating enrichment of the ABC expression profile in independent clinical precancer specimens. We then show that capivasertib, a clinically approved kinase inhibitor, prevented the emergence of the abnormal phenotype and the accumulation of cells with an active DNA damage response. Further, capivasertib reversed the established phenotype; and remained effective when nebulised in vitro, mimicking therapeutic inhalation. Together, these findings establish a tractable human model of carcinogen-induced early LUSC and provide a proof-of-principle for repurposing targeted therapies for the prevention of lung cancer.
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BibTeX
@misc{guo2026carcinogeninduced,
title = {{Carcinogen-induced preinvasive human squamous lung cancer is characterised by a novel atypical basal cell state and presents opportunities for chemoprevention}},
author = {W. Guo and H. Giles and A. Chernaik and Y. Memari and J. Xie and D. Black and A. Hilgendorff and C. Gabriel and A. O. Yildirim and H. Davies and M. Goddard and L. D'Sa and O. Schmid and S. Nik-Zainal and N. Han and F. McCaughan},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.748423},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.748423v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Carcinogen-induced preinvasive human squamous lung cancer is characterised by a novel atypical basal cell state and presents opportunities for chemoprevention
AU - W. Guo
AU - H. Giles
AU - A. Chernaik
AU - Y. Memari
AU - J. Xie
AU - D. Black
AU - A. Hilgendorff
AU - C. Gabriel
AU - A. O. Yildirim
AU - H. Davies
AU - M. Goddard
AU - L. D'Sa
AU - O. Schmid
AU - S. Nik-Zainal
AU - N. Han
AU - F. McCaughan
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.748423
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.748423v1
AB - There are no adequate carcinogen-induced models of the earliest stages of human squamous lung cancer (LUSC), limiting the development of effective chemoprevention strategies. We developed a novel human model of early LUSC by exposing differentiated primary human airway cells to a chemical carcinogen known to cause murine LUSC. Carcinogen exposure induced a phenotype recapitulating the earliest stages of human LUSC and associated with the emergence of a novel population of atypical basal cells (ABCs). ABCs express key cancer hallmark markers but without evidence of either common LUSC-associated mutations or an emergent major clonal/subclonal population. We established the clinical relevance of this model by demonstrating enrichment of the ABC expression profile in independent clinical precancer specimens. We then show that capivasertib, a clinically approved kinase inhibitor, prevented the emergence of the abnormal phenotype and the accumulation of cells with an active DNA damage response. Further, capivasertib reversed the established phenotype; and remained effective when nebulised in vitro, mimicking therapeutic inhalation. Together, these findings establish a tractable human model of carcinogen-induced early LUSC and provide a proof-of-principle for repurposing targeted therapies for the prevention of lung cancer.
ER -