Harvard builds a portfolio of targeted drugs for non-small cell lung cancer

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Harvard builds a portfolio of targeted drugs for non-small cell lung cancer

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More than 5000 kinds: Harvard Medical School builds a portfolio of targeted drugs for non-small cell lung cancer.

The combination of anticancer drugs is widely regarded as a way to overcome the limited efficacy of single drugs. However, the design and testing of drug combinations is very challenging.

Recently, researchers from Harvard Medical School published a research paper entitled “A landscape of response to drug combinations in non-small cell lung cancer” in the journal “Nature Communications”.

The study constructed a large data set , More than 5,000 targeted drug combinations were screened in 81 non-small cell lung cancer cell lines.

Our analysis reveals profound heterogeneity of tumor model responses and dissects genetic and cellular network determinants of combined effects.

Furthermore, this dataset will provide a common foundational resource for the scientific community interested in the combination development of anticancer drugs, as well as for the development of computational modeling methods for the systematic discovery of synergistic effects in cancer cells.

https://www.nature.com/articles/s41467-023-39528-9

Research Background

Modern treatment approaches for many pathologies include the use of drug combinations for better efficacy and reduced systemic toxicity in patients. Drug combinations are often used to treat microbial infections.

In addition, drug combinations are often part of anticancer treatment based on decades of empirical clinical findings.

Rationally designed targeted agents are now approved for the treatment of a variety of cancers, but the vast majority of patients are still first treated with combinations of “classic” genotoxic chemotherapy drugs.

Targeted drugs are sometimes used in combination with traditional cytotoxic drugs: for example, the targeted drug trastuzumab (an antibody against HER2) is combined with taxanes to achieve higher efficacy in treating HER2 breast cancer.

Currently, only a few fully rationally designed targeted drug combinations are used to treat cancer.

However, there have been some notable recent successes: In estrogen receptor (ER)-positive breast cancer, combining CDK4/6 inhibition with estrogen receptor (ER)-directed therapy is more beneficial than other treatments.

Combination of BRAF and MEK1/2 inhibitors improves melanoma outcomes. Many other targeted combinations are currently being tested in clinical trials.

While combining targeted agents can improve benefit, the rational development of drug combinations remains hampered by limited understanding of the underlying cellular processes.

There is now ample evidence of heterogeneity in response to targeted anticancer therapy, even among molecularly stratified patients.

In fact, among the best responding patient cohorts, responses remain highly variable, either initially ineffective (innate resistance) or limited and unpredictable in duration (acquired resistance).

It is unclear whether combination therapy with targeted agents would show heterogeneity of response or allow for a broader range of treatment options.

Even for targeted drugs, another key concern is toxicity. To achieve higher efficacy than single agents and minimize systemic toxicity, drug combinations with specific synergistic effects in cancer cells are conceptually attractive, even though obtaining potent combinations in patient cohorts does not require synergy.

Research process

In this paper, researchers describe the results of a very large combination drug screen of more than 5,000 drug combinations in 81 highly characterized NSCLC cell lines, some of which were further tested in additional validation screens .

By mining the literature of published drug combinations and using knowledge of cellular circuits, the researchers demonstrate the validity of the data and analysis strategy. Overall, the researchers captured a large number of known coordinated events that are consistent with prior knowledge.

Some of this was supported by an integrated pivotal analysis of tumor data from NSCLC patients, suggesting potential translational relevance.

To ensure the robustness of the screening results, the researchers performed a small-scale validation screen using a different live-cell assay than the initial large-scale screen. In addition, the investigators conducted a validation screen at a different institution than the primary screen.

The researchers found that each core drug exhibited strong synergy with the expected library drugs in different cell lines.

Consistent with this, the researchers observed that the most common synergistic combinations were recaptured in validation screens. Taken together, these results support the robustness of the main dataset.

To prioritize less toxic drug combinations, the researchers tested the 29 drug combinations used in the validation screen on a pair of immortalized non-cancer cell lines and identified a subset of them that were effective against cancer cell Selectively effective or synergistic.

However, given the apparent limitations of using cell lines for toxicity studies, further in vivo experiments are needed to assess their toxicity and further prioritize combinations for translational studies.

Overview of Research Screening Strategies

Significance

In conclusion, this work constructs and analyzes a large-scale dataset of drug combinations in lung cancer. This dataset is fully accessible to the scientific community, greatly expanding the previously publicly available resource of drug combinations for mining and modeling. Further analysis can be performed using the data here.

Beyond that, the researchers hope the data will advance the development of additional analyzes and new computational methods that advance predictions about drug combination outcomes and deepen our understanding of the rules underlying beneficial drug interactions in cancer.

References:

https://www.nature.com/articles/s41467-023-39528-9

Harvard builds a portfolio of targeted drugs for non-small cell lung cancer

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