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Updated: May 13, 2025
Radiosensitivity of Cancer Stem Cells in Lung Cancer Cell Lines
Published on: August 21, 2019
Multifactorial stroma-mediated resistance is a major contributor to residual disease under targeted therapies in lung
Bina Desai1,2, Tatiana Miti3, Sandhya Prabhakaran3
1Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Centre and Research Institute; Tampa, FL, USA.
Abstract:
Despite inducing strong and durable clinical responses, targeted therapies do not eliminate advanced cancers, as a subset of tumor cells survives within residual tumors, eventually developing resistance. The ability of tumor cells to avoid therapeutic elimination can be mediated both by cell-intrinsic and microenvironmental mechanisms. Whilst the specific molecular mediators of cell-intrinsic and microenvironmental resistance are well understood, their relative contribution to in vivo therapeutic responses remains poorly defined. Using spatial histological inferences from experimental models of ALK+ NSCLC, we found that peristromal niches protected tumor cells from therapeutic elimination in vivo, enabling in vivo persistence. Whereas the development of bona fide resistance is associated with the development of the development of cell-intrinsic resistance, relapse of tumor growth reflects a combined effect of both cell-intrinsic and microenvironmental mechanisms. Mechanistically, the protective effect of the peristromal niche is not reducible to a single mechanism, instead reflecting a combined effect of multiple juxtacrine and paracrine mediators. The lack of reducibility to a single molecular mediator presents an obvious challenge to the therapeutic paradigms of targeting individual resistance mechanisms. We found that this challenge could be mitigated by shifting the therapeutic focus to orthogonal collateral sensitivities of residual tumors. Exploiting adaptive upregulation of HER2, associated with both cell-intrinsic and microenvironmental persistence, using the antibody-drug conjugate T-DXd strongly enhanced the effect of targeted therapies and suppressed the development of resistance.
Insights
Targeted therapies leave cancer cells surviving in protective tumor microenvironments. Combining therapies targeting collateral sensitivities, like HER2, can overcome resistance and improve treatment outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- Targeted therapies induce responses but fail to eliminate advanced cancers due to surviving tumor cells.
- Mechanisms of tumor cell resistance involve both cell-intrinsic and microenvironmental factors.
- The relative contribution of these resistance mechanisms to in vivo therapeutic outcomes is not well understood.
Purpose of the Study:
- To investigate the role of the tumor microenvironment in therapeutic resistance.
- To identify strategies to overcome resistance to targeted therapies in ALK+ non-small cell lung cancer (NSCLC).
Main Methods:
- Utilized spatial histological inferences from experimental models of ALK+ NSCLC.
- Analyzed the impact of peristromal niches on tumor cell persistence and resistance.
- Investigated the efficacy of targeting collateral sensitivities, specifically HER2 upregulation, using T-DXd.
Main Results:
- Peristromal niches protect tumor cells from therapeutic elimination in vivo, contributing to persistence.
- Tumor relapse results from a combination of cell-intrinsic and microenvironmental resistance mechanisms.
- Targeting adaptive HER2 upregulation with T-DXd synergized with targeted therapies, enhancing efficacy and suppressing resistance.
Conclusions:
- The tumor microenvironment, specifically peristromal niches, plays a critical role in enabling tumor cell survival and resistance to targeted therapies.
- Therapeutic strategies should consider targeting orthogonal collateral sensitivities to overcome resistance, rather than focusing on single mechanisms.
- Combining targeted therapies with agents like T-DXd, which exploit adaptive resistance mechanisms such as HER2 upregulation, offers a promising approach to improve cancer treatment outcomes.
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