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; Heidi M Haikala

doi:10.1038/s41467-024-55378-5

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

Nat Commun. 2025 Jan 2;16(1):28. doi: 10.1038/s41467-024-55378-5.

Authors

Bassel Alsaed^{1

2}, Linh Lin^{1

2}, Jieun Son^{3

4}, Jiaqi Li^{3

4}, Johannes Smolander^{1

2

5}, Timothy Lopez^{3

4}, Pinar Ö Eser^{3

4}, Atsuko Ogino^{3

4}, Chiara Ambrogio⁶, Yoonji Eum^{3

4}, Tran Thai^{3

4}, Haiyun Wang⁷, Eva Sutinen^{8

9}, Hilma Mutanen^{1

2}, Hanna Duàn^{1

2

5}, Nina Bobik^{1

2}, Kristian Borenius¹⁰, William W Feng^{3

4}, Behnam Nabet^{11

12}, Satu Mustjoki^{1

2

5}, Sanna Laaksonen¹³, Benjamin K Eschle^{3

14}, Michael J Poitras^{3

14}, David Barbie^{3

4}, Ilkka Ilonen^{2

10}, Prafulla Gokhale^{3

13}, Pasi A Jänne^#^{3

4}, Heidi M Haikala^#^{15

16

17

18}

Affiliations

¹ Translational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
² iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
⁶ Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
⁷ School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁸ Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
¹⁰ Department of General Thoracic and Esophageal Surgery, Heart and Lung Center, Helsinki University Hospital & University of Helsinki, Helsinki, Finland.
¹¹ Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹² Department of Pharmacology, University of Washington, Seattle, WA, USA.
¹³ Department of Pathology, Helsinki University Hospital & University of Helsinki, Helsinki, Finland.
¹⁴ Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Translational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland. [email protected].
¹⁶ iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. [email protected].
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁸ Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Cancer-Associated Fibroblasts / drug effects
Cancer-Associated Fibroblasts / metabolism
Cancer-Associated Fibroblasts / pathology
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm* / genetics
Epithelial-Mesenchymal Transition / drug effects
Epithelial-Mesenchymal Transition / genetics
ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / genetics
ErbB Receptors* / metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Mutation
Protein Kinase Inhibitors* / pharmacology
Transforming Growth Factor beta / metabolism
Tumor Microenvironment* / drug effects
Tumor Microenvironment* / genetics

Substances

ErbB Receptors
EGFR protein, human
Protein Kinase Inhibitors
Transforming Growth Factor beta
Antineoplastic Agents

Abstract

MeSH terms

Substances

Grants and funding