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Peer-reviewedCC BY-NC-NDNature Communications

Multifactorial sheltering in peristromal niches shapes in vivo responses of lung cancers to targeted therapies

  • Bina Desai1,2
  • Tatiana Miti3
  • Sandhya Prabhakaran3
  • Daria Miroshnychenko2
  • Pragya Kumar2
  • Menkara Henry2
  • Viktoriya Marusyk2
  • Natália Souza Nunes Siqueira2
  • Chandler Gatenbee3
  • Hilal Özakıncı4
  • Marilyn Bui5,6
  • Theresa A. Boyle5,4
7 more authors
  • Jacob Scott7
  • Philipp M. Altrock8
  • Bruna Pellini4,9
  • Eric B. Haura4
  • Alexander R.A. Anderson3
  • David Basanta3
  • Andriy Marusyk10,11
11 affiliations
  1. 1Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
  2. 2Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  3. 3Department of Integrated Mathematical Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  4. 4Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  5. 5Department of Machine Learning, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  6. 6Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  7. 7Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA
  8. 8Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany
  9. 9Department of Thoracic Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
  10. 10Department of Molecular Medicine, University of South Florida, Tampa, FL, USA. [email protected]
  11. 11Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. [email protected]
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Abstract

Targeted therapies directed against oncogenic signaling addictions, such as inhibitors of ALK in ALK+ NSCLC often induce strong and durable clinical responses. However, they are not curative in metastatic cancers, as some tumor cells persist through therapy, eventually developing resistance. Therapy sensitivity can reflect not only cell-intrinsic mechanisms but also inputs from stromal microenvironment. Yet, the contribution of tumor stroma to therapeutic responses in vivo remains poorly defined. To address this gap of knowledge, we assessed the contribution of stroma-mediated resistance to therapeutic responses to the frontline ALK inhibitor alectinib in xenograft models of ALK+ NSCLC. We found that stroma-proximal tumor cells are partially protected against cytostatic effects of alectinib. This effect is observed not only in remission, but also during relapse, indicating the strong contribution of stroma-mediated resistance to both persistence and resistance. This therapy-protective effect of the stromal niche reflects a combined action of multiple mechanisms, including growth factors and extracellular matrix components. Consequently, despite improving alectinib responses, suppression of any individual resistance mechanism was insufficient to fully overcome the protective effect of stroma. Focusing on shared collateral sensitivity of persisters offered a superior therapeutic benefit, especially when using an antibody-drug conjugate with bystander effect to limit therapeutic escape. These findings indicate that stroma-mediated resistance might be the major contributor to both residual and progressing disease and highlight the limitation of focusing on suppressing a single resistance mechanism at a time.

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Cite

BibTeXRIS
BibTeX
@article{desai2026multifactorial,
  title = {{Multifactorial sheltering in peristromal niches shapes in vivo responses of lung cancers to targeted therapies}},
  author = {Bina Desai and Tatiana Miti and Sandhya Prabhakaran and Daria Miroshnychenko and Pragya Kumar and Menkara Henry and Viktoriya Marusyk and Natália Souza Nunes Siqueira and Chandler Gatenbee and Hilal Özakıncı and Marilyn Bui and Theresa A. Boyle and Jacob Scott and Philipp M. Altrock and Bruna Pellini and Eric B. Haura and Alexander R.A. Anderson and David Basanta and Andriy Marusyk},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-73454-w},
  url = {https://doi.org/10.1038/s41467-026-73454-w},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Multifactorial sheltering in peristromal niches shapes in vivo responses of lung cancers to targeted therapies
AU  - Bina Desai
AU  - Tatiana Miti
AU  - Sandhya Prabhakaran
AU  - Daria Miroshnychenko
AU  - Pragya Kumar
AU  - Menkara Henry
AU  - Viktoriya Marusyk
AU  - Natália Souza Nunes Siqueira
AU  - Chandler Gatenbee
AU  - Hilal Özakıncı
AU  - Marilyn Bui
AU  - Theresa A. Boyle
AU  - Jacob Scott
AU  - Philipp M. Altrock
AU  - Bruna Pellini
AU  - Eric B. Haura
AU  - Alexander R.A. Anderson
AU  - David Basanta
AU  - Andriy Marusyk
PY  - 2026
DA  - 2026/05/29
JO  - Nature Communications
DO  - 10.1038/s41467-026-73454-w
UR  - https://doi.org/10.1038/s41467-026-73454-w
AB  - Targeted therapies directed against oncogenic signaling addictions, such as inhibitors of ALK in ALK+ NSCLC often induce strong and durable clinical responses. However, they are not curative in metastatic cancers, as some tumor cells persist through therapy, eventually developing resistance. Therapy sensitivity can reflect not only cell-intrinsic mechanisms but also inputs from stromal microenvironment. Yet, the contribution of tumor stroma to therapeutic responses in vivo remains poorly defined. To address this gap of knowledge, we assessed the contribution of stroma-mediated resistance to therapeutic responses to the frontline ALK inhibitor alectinib in xenograft models of ALK+ NSCLC. We found that stroma-proximal tumor cells are partially protected against cytostatic effects of alectinib. This effect is observed not only in remission, but also during relapse, indicating the strong contribution of stroma-mediated resistance to both persistence and resistance. This therapy-protective effect of the stromal niche reflects a combined action of multiple mechanisms, including growth factors and extracellular matrix components. Consequently, despite improving alectinib responses, suppression of any individual resistance mechanism was insufficient to fully overcome the protective effect of stroma. Focusing on shared collateral sensitivity of persisters offered a superior therapeutic benefit, especially when using an antibody-drug conjugate with bystander effect to limit therapeutic escape. These findings indicate that stroma-mediated resistance might be the major contributor to both residual and progressing disease and highlight the limitation of focusing on suppressing a single resistance mechanism at a time.
SN  - 2041-1723
ER  -