July: Personalized Medicine in Breast Cancer

New kid on the block: receptor tyrosine kinase inhibitors as a potential treatment for triple-negative breast cancer

Matthew Borrelli, MSc.
Contact: mborrel2@uwo.ca
July 30, 2021

Cancers are just as unique as the individuals who fight them: we can say with certainty that no two are perfectly alike. However, research advances increasingly allow us to categorize different subtypes of cancer based on how they differ from healthy tissue at a molecular level. Highly specific disease categorization is the basic concept underlying personalized medicine, the practice of which ultimately aims to deliver treatment with the highest chance of success based on the genetic/molecular “fingerprint” of the cancer in question.

A hallmark example of cancer categorization is the differentiation of breast cancers based on the receptor proteins they have (Perou et al., 2000). Receptor proteins allow cells to respond to various hormones, growth factors, and other molecular signals in the body, and all cells in the body have a variety of these proteins. Particularly relevant in the case of breast cancers are the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), since a number of highly effective drug treatments target these receptors.

Certain breast cancers can adapt to survive without these receptors, limiting treatment options. Breast cancers that have stopped producing all three receptors (ER, PR, and HER2) are termed triple-negative breast cancers (TNBC), and TNBCs make up 15-20% of cases (Foulkes et al., 2010). TNBC has the lowest five-year survival rate among breast cancer subtypes (Fallahpour et al., 2017), highlighting the difficulty in treating it and the importance of identifying new ways to target it. One characteristic of TNBCs with high therapeutic potential is the frequent over-production of receptor proteins called receptor tyrosine kinases (RTKs) (Lehmann et al., 2011), which can play an important role in promoting cell division, and thus, tumour growth (Lemmon et al., 2010).

Figure 1. Comparison of targetable receptors in non- triple-negative breast cancers (TNBC) compared to TNBC. TNBC, triple-negative breast cancer; HER-2, human epidermal growth factor receptor 2; ER, estrogen receptor; PR, progesterone receptor; RTKs, receptor tyrosine kinases; extracellular, outside the cell; intracellular, inside the cell.

MD/PhD Candidate, Cory Lefebvre of Dr. Alison Allan’s laboratory at Victoria Hospital’s Cancer Research Laboratory Program is currently investigating the potential use of drugs that block the activity of specific RTKs (RTK inhibitors) in models of TNBC, and why these drugs sometimes become less effective over time. His recent publication (2021) outlines the importance of shifting towards personalized medicine approaches for cancer treatment. Two RTKs, called epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), are found in higher amounts in TNBCs compared with other breast cancer subtypes (Lehmann et al., 2011) and, therefore, were the targets for this investigation of RTK inhibition in TNBC cells.

Lefebvre tested the effects of two RTK inhibitors – one that inhibits EGFR, and one that inhibits c-Met – in two TNBC cell lines (established from different TNBC tumours for laboratory use). Although it’s understood that, on average, TNBCs have higher levels of RTKs than other breast cancer subtypes, that doesn’t mean that every TNBC has high levels of every RTK. To begin the study, levels of EGFR and c-Met in each cell line were determined, revealing that the two cell lines had very different levels of these RTKs. One cell line had lots of EGFR and very little c-Met, while the other cell line had very little EGFR but lots of c-Met.

The difference in receptor levels between the two cell lines proved to be an important factor in their response to the RTK inhibitors. The cells with lots of EGFR were more than 500 times as sensitive to the EGFR inhibitor as the other cells, and the cells with lots of c-Met were much more sensitive to the c-Met inhibitor. Both drugs had the effect of slowing growth in the cell lines that were sensitive to them, a desirable outcome for a potential cancer treatment. To determine what was happening inside the cells to slow them down, Lefebvre looked for signs of RTK activity in cells exposed to the drugs, to verify that they were being inhibited as predicted. It turned out that the drug treatments each blocked activation of a protein with direct effects on cell/tumour growth, that would normally be activated by the targeted/blocked RTKs.

On the surface, these findings tell us that if a cancer has high levels of a certain RTK, it may be more likely to respond to treatments targeting that same RTK. While this conclusion is logical, understanding that these effects may be mediated predominantly by other proteins provides important insight to help tackle another major challenge in the treatment of TNBC: acquired resistance. Acquired resistance is a term used to describe how cancers can sometimes become unresponsive (resistant) to therapies that were once effective. In the context of RTK inhibitors and TNBC, even if the inhibitor is initially effective at blocking its target, the cancer may become resistant by producing a different version of the RTK that cannot be blocked by the drug. This type of resistance makes effective treatment extremely difficult and showcases the importance of Lefebvre’s work with Dr. Allan.

This work, and that of others in this research area, also provides a rationale for expanded screening of cancers in the clinical setting. “There is no further molecular profiling done beyond initial assessment of ER/PR/HER-2 receptor status,” Lefebvre says of current methods for TNBC characterization. “I think that as targeted therapeutics are developed and demonstrate utility in treating TNBC, then there will be more importance in including those targets, like RTKs, in molecular profiling.”

At present, there are no RTK inhibitors used to treat TNBC in the clinic, but research is underway to determine which ones might be most effective for which cancers. The precedent for targeting RTKs in other types of cancer has been set, though: inhibitors of HER-2, an RTK that is lost in TNBC, have been successful in the treatment of HER-2-positive cancers.

Looking to the future as his research progresses, Lefebvre hopes to develop a “big picture” approach to learn more about acquired resistance to RTK inhibitors by taking a snapshot of all of a cancer cell’s proteins at once, using a technique called mass spectrometry. “Perhaps, one day, this approach may be incorporated in the management of recurrent TNBC tumours that have developed resistance and, through identification of potential mediators of said resistance, guide treatment strategies to overcome [it].”

Original article

Lefebvre, C., & Allan, A. (2021). Anti-proliferative and anti-migratory effects of EGFR and c-Met tyrosine kinase inhibitors in triple negative breast cancer cells. Precision Cancer Medicine, 4. doi:10.21037/pcm-20-62


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