Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment

Bassel Alsaed, Linh Lin, Jieun Son, Jiaqi Li, Johannes Smolander, Timothy Lopez, Pinar Ö. Eser, Atsuko Ogino, Chiara Ambrogio, Yoonji Eum, Tran Thai, Haiyun Wang, Eva Sutinen, Hilma Mutanen, Hanna Duàn, Nina Bobik, Kristian Borenius, William W. Feng, Behnam Nabet, Satu Mustjoki, Sanna Laaksonen, Benjamin K. Eschle, Michael J. Poitras, David Barbie, Ilkka Ilonen, Prafulla Gokhale, Pasi A. Jänne and Heidi M. Haikala ()
Additional contact information
Bassel Alsaed: University of Helsinki
Linh Lin: University of Helsinki
Jieun Son: Dana-Farber Cancer Institute
Jiaqi Li: Dana-Farber Cancer Institute
Johannes Smolander: University of Helsinki
Timothy Lopez: Dana-Farber Cancer Institute
Pinar Ö. Eser: Dana-Farber Cancer Institute
Atsuko Ogino: Dana-Farber Cancer Institute
Chiara Ambrogio: University of Torino
Yoonji Eum: Dana-Farber Cancer Institute
Tran Thai: Dana-Farber Cancer Institute
Haiyun Wang: Tongji University
Eva Sutinen: University of Helsinki
Hilma Mutanen: University of Helsinki
Hanna Duàn: University of Helsinki
Nina Bobik: University of Helsinki
Kristian Borenius: Helsinki University Hospital & University of Helsinki
William W. Feng: Dana-Farber Cancer Institute
Behnam Nabet: Fred Hutchinson Cancer Center
Satu Mustjoki: University of Helsinki
Sanna Laaksonen: Helsinki University Hospital & University of Helsinki
Benjamin K. Eschle: Dana-Farber Cancer Institute
Michael J. Poitras: Dana-Farber Cancer Institute
David Barbie: Dana-Farber Cancer Institute
Ilkka Ilonen: iCAN Digital Precision Cancer Medicine Flagship
Prafulla Gokhale: Dana-Farber Cancer Institute
Pasi A. Jänne: Dana-Farber Cancer Institute
Heidi M. Haikala: University of Helsinki

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.

Date: 2025
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DOI: 10.1038/s41467-024-55378-5

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