Paclitaxel is one of the most effective chemotherapy drugs for breast cancer. It is used for breast cancer in the early stages as well as for metastatic breast cancer, in combination with other chemotherapeutic agents or as a neoadjuvant. Although it is commonly understood to act as a microtubule poison and lead to mitotic arrest, this knowledge is largely based on studies of cells in culture, with drug concentrations that may not be realistic.
In a recent study, researchers led by Beth Weaver from the University of Wisconsin, Madison (UW-M) show that paclitaxel treatment in breast cancer patients increased cell division with chromosome missegregation to induce cytotoxicity. They also found that increased chromosomal instability in tumor cells before treatment was predictive of response to paclitaxel therapy. The study was published online in the September 8, 2021, issue of Science Translational Medicine.
Weaver is an associate professor in the Department of Cell and Regenerative Biology, School of Medicine and Public Health, UW-M and the senior author of the paper. Her group works on regulation of chromosome segregation during mitosis and the impact of chromosome missegregation on tumors.
"A major issue with the clinical efficacy of paclitaxel is that in breast cancer, where it is used as a single agent by itself, only about half of the breast cancer patients benefit and currently there is no way to predict which patients those will be," Weaver told BioWorld Science. "So everyone gets treated and the patients that don't benefit are still subjected to potentially very serious side effects." The authors sought to identify a biomarker by elucidating the mechanism of action of paclitaxel to be able to predict which patients would respond to paclitaxel therapy and which patients would not.
Weaver and her colleagues have previously shown that paclitaxel levels in primary breast tumors are well below those required to cause mitotic arrest. Instead, cells exposed to these lower concentrations of drug proceed through mitosis and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. They also showed that mitotic arrest is dispensable for tumor regression in patients.
In the present study, the authors demonstrate that clustering of multipolar spindles represents a major mechanism of paclitaxel resistance. Increasing the duration of spindle multipolarity increased the likelihood of chromosome missegregation and cell death.
The authors achieved increased spindle multipolarity in breast cancer cells both pharmacologically (using an inhibitor of the kinesin-like protein HSET) and genetically by centrosome amplification. Weaver said this indicates that "treatments that prevent cells from focusing paclitaxel-induced multipolar spindles into bipolar spindles are likely to improve paclitaxel efficacy."
Weaver stressed that "the importance of paclitaxel-induced multipolar spindles is their ability to induce chromosomal instability. If we can induce low, tolerated rates of chromosomal instability in the cancer cells, that can potentiate paclitaxel efficacy translatable to patient tumors."
Weaver added that "chromosomal instability is predictive of whether a given tumor will respond to paclitaxel or similar drugs, and this is important because it suggests it could be used as a biomarker. Pretreatment chromosomal instability can be used as a predictive biomarker of paclitaxel response. Such a biomarker would substantially improve patient outcomes by sparing nonresponders' paclitaxel-associated toxicities and reducing delays in receiving effective treatment."
Weaver's study also identified cellular proteins involved in refocusing of the abnormal mitotic spindles that leads to paclitaxel resistance. Weaver said that "this is important for two reasons - one is that if we understand what determines whether those spindles are going to focus or not, we could use that to improve a chromosomal instability-based biomarker. Also, once we identify the proteins involved in that focusing, we could use those as novel drug targets and develop new drugs that would prevent that focusing, and therefore sensitize resistant cancers."
The authors also showed that inhibition of the kinase monopolar spindle 1 (Mps1) decreased chromosomal instability and cell death in MDA-MB-231 breast cancer cells treated with clinically relevant concentrations of paclitaxel due to a decrease in multipolar divisions. Interestingly, in otherwise unmanipulated cells, Mps1 weakens the mitotic checkpoint and causes chromosomal instability.
According to Weaver, "It is difficult to get people excited about paclitaxel because it is an old drug. It is off-patent, which I think is fantastic. Because it means that it is inexpensive and it is accessible, and clinicians have a lot of experience with it. Even with immunotherapy and targeted therapies, paclitaxel remains a cornerstone of anticancer treatment. It is received by many patients and there is really a window and opportunity here for us to improve patient outcomes." Weaver believes that future studies of a larger homogeneous cohort of patients will permit a more robust test of chromosomal instability as a predictive biomarker and improve clinical outcomes for paclitaxel regimens in breast cancer.