Collateral sensitivity networks reveal evolutionary instability and novel treatment strategies in ALK mutated non-small cell lung cancer
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Abstract
Drug resistance remains an elusive problem in cancer therapy, particularly for novel targeted therapies. Much work is focused upon the development of an arsenal of targeted therapies, towards oncogenic driver genes such as ALK-EML4, to overcome the inevitable resistance that develops over time. Currently, after failure of first line ALK TKI therapy, another ALK TKI is administered, though collateral sensitivity is not considered. To address this, we evolved resistance in an ALK rearranged non-small cell lung cancer line (H3122) to a panel of 4 ALK TKIs, and performed a collateral sensitivity analysis. All ALK inhibitor resistant cell lines displayed significant cross-resistance to all other ALK inhibitors. We then evaluated ALK-inhibitor sensitivities after drug holidays of varying length (1–21 days), and observed dynamic patterns of resistance. This unpredictability led us to an expanded search for treatment options, where we tested 6 further anti-cancer agents for collateral sensitivity among resistant cells, uncovering possibilities for further treatment, including cross-sensitivity to standard cytotoxic therapies, as well as Hsp90 inhibitors. Taken together, these results imply that resistance to targeted therapy in non-small cell lung cancer is highly dynamic, and also one where there are many opportunities to re-establish sensitivities where there was once resistance. Drug resistance in cancer inevitably emerges during treatment; particularly with novel targeted therapies, designed to inhibit specific molecules. A clinically-relevant example of this phenomenon occurs in ALK-positive non-small cell lung cancer, where targeted therapies are used to inhibit the ALK-EML4 fusion protein. A potential solution to this may lie in finding drug sensitivities in the resistant population, termed collateral sensitivities, and then using these as second-line agents. This study shows how the evolution of resistance in ALK-positive lung cancer is a dynamic process through time, one in which patterns of drug resistance and collateral sensitivity change substantially, and therefore one where temporal regimens, such as drug cycling and drug holidays may have great benefit.
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A variety of evolutionary trajectories can lead to the same phenotype.
“As seen in experimental and natural evolution, a variety of evolutionary trajectories can lead to the same phenotype11–14.”
From Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature (2023) · cites this paper as [13]
The Introduction discusses stochastic evolution of drug resistance and variation in phenotypes, but does not say that different evolutionary trajectories lead to the same phenotype. The Discussion says that testing the repeatability of resistance patterns would require multiple biological replicates. Searches for evolutionary trajectories and phenotype found no passage establishing the attributed claim. (LLM, conf=0.70)
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- Authors
- Dhawan, A., Nichol, D., Kinose, F., Abazeed, M. E., Marusyk, A., Haura, E. B., & Scott, J. G.
- Affiliations
- Cleveland Clinic (US)
- Moffitt Cancer Center (US)
- Corresponding author
- Scott, Jacob G.
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-04-27
- Volume
- 7
- Issue
- 1
- Pages
- 1232-1232
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5430816
- OpenAlex
- W2527582579
- Cited by
- 79
- References
- 32
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 14 · 2019: 10 · 2018: 15 · 2017: 2
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- Engineering and Physical Sciences Research Council (1354441)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- collateral sensitivity, ALK rearrangement, non-small cell lung cancer, ALK inhibitors, drug resistance, cross-resistance, Hsp90 inhibitors, drug holidays, second-line therapy, resistance evolution
- MeSH terms
- Anaplastic Lymphoma Kinase, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Drug Resistance, Neoplasm, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Protein Kinase Inhibitors
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