Gene Expression Plays a Role in Response to Cancer Treatment

Combining cancer drugs may help prevent drug resistance.

Despite the same diagnosis, treatment for cancer can vary due to a number of factors, including patient preference and genetics.

The variability of tumor response to cancer drugs is largely hidden, but new findings from a study published by Nature Communications may provide insight into why patients have differing responses to the same drug.

The new findings highlight strategies that can be used to evaluate the efficacy of cancer drugs and develop combinations that prevent cancer from evading treatment, according to the study authors.

The authors analyzed more than 600 drug and breast cancer cell combinations and found that drug exposure causes significant gene expression alterations but do not affect cell growth or survival, according to the study. Normally, these changes would signal that the drugs were working.

The authors hypothesize that it was the result of adaptive resistance mechanism, which can be inhibited when properly identified.

“Our findings suggest new ways of tackling the still-difficult task of working out which patients should receive which drug and how drugs should be combined to maximize therapeutic benefit,” said senior study author Peter Sorger, PhD.

Included in the study were gene expression data from 6 different breast cancer cell lines, which were exposed to 109 different drugs. The authors evaluated cell growth and survival with a model that adjusts for variations.

The investigators identified nearly 8000 gene expression signatures that were compared across different factors of drug response, including by cell line, drug class, pathway, cellular function, and more, according to the study.

The authors noted that cell lines responded to drugs in 2 patterns: One group of drugs had a similar response across all cells, while the other resulted in a more specific response, according to the study.

The second group of drugs resulted in a response that was specific to cell type. These drugs targeted the signaling pathways that are disrupted by mutations, including trametinib, which inhibits MEK pathways.

“We find that drug-sensitive tumor cells respond in similar ways to some classes of drugs and very different ways to other classes of drugs,” Dr Sorger said. “This was unexpected and suggests fundamental but unrecognized differences in drug action in tumor cells from different individuals having the same disease—in this case, breast cancer.”

Although gene expression in most pairings was linked to cancer survival, approximately 3% had a significant change in cancer cell gene expression, according to the study.

In an estrogen receptor-negative cell line, cancer cells continued to grow in response to trametinib and alpelisib monotherapy, even when exposed to high doses. Notably, a combination of the drugs was found to have a strong synergistic effect that resulted in cell death, according to the study.

Further analyses showed that certain classes of drugs caused molecular changes that allowed the cells to bypass the drug’s mechanisms, making it less effective. The authors discovered that the addition to trametinib prevented the resistance pathway.

“Gene expression profiling allows us to identify drugs that are potentially useful when given in combination. If we had measured only cell survival, it would seem as though each drug was ineffective on its own and should be ignored,” said co-lead author Marc Hafner, PhD. “The cells can cope when exposed to one of these drugs, but when both are put together, the response is strong enough to stop cell growth and induce death.”

These findings highlight the importance of gene expression analysis to discover mechanisms that could result in resistance.

This analysis may lead to new efforts to create individualized treatments based on the molecular characteristics of each patient’s tumor, according to the study.

“Our study is not a recipe for generating effective drug combinations, but it can help narrow down candidates and identify which drugs might be most promising when tested in combination,” Dr Hafner said. “In order to go beyond targeting an oncogene and just hoping for the best, we need to understand the actual biological effects of drugs inside cells. That’s how we can have better and smarter use of drugs.”