PARP inhibitors can improve the survival of breast cancer patients with BRAC1/2 mutations, but the drugs will eventually stop working and the cancer will recur. Recently, in a research report titled "FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer" published in the international journal EMBO Molecular Medicine, scientists from Columbia University and other institutions discovered a new cancer drug that can prevent or slow the recurrence of cancer by studying cancer-bearing mice.
"The problem so far is that patients' response to PARP inhibitors is not long-lasting, sometimes it lasts for six months, sometimes it lasts a little longer." Researcher Professor Swarnali Acharyya said, "But oncologists tell me that almost all cancer patients will eventually relapse, so it is crucial to clarify the reasons behind it." According to the National Cancer Institute, more than 60% of women who inherit mutations in BRCA1 and BRCA2 will develop breast cancer in their lifetime. PARP inhibitors work by targeting PARP proteins, which help cancer cells repair damaged DNA and promote their continued growth.
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It is well known that cancer cells can use a variety of mechanisms to overcome PARP inhibitors. But in this study, researchers have identified for the first time a novel mechanism that can be exploited by current drugs, such as axitinib, an FDA-approved drug for the treatment of metastatic kidney cancer. To understand how BRCA cancers become resistant to PAPR inhibitors, the researchers developed new mouse models. These models respond to PAPR inhibitors in much the same way as patients do, with both producing a striking response to the drugs before the cancer acquires resistance and relapses.
Figure 1. FLT1 as a potential biomarker and therapeutic target for reversing PARPi resistance in BRCA-mutant breast cancer. (Tai Y, et al., 2024)
When the researchers analyzed the drug-resistant cancers from these mice, they noticed something strange. "When we took drug-resistant cancer cells from the tumor and treated them with PARP inhibitors in the lab, they died," said Acharyya, a researcher at the Institute for Oncology. "So our next question was, why do cells that are resistant to drugs in vivo die in vitro?" The answer may be found in the tumor microenvironment. When mice were treated with PARP inhibitors, normal cells around the tumor secreted a special protein called PGF, which may be a stress response. However, this protein then binds to the FLT1 receptor on the cancer cells, promoting cancer growth and driving away T cells that fight cancer.
When the researchers blocked the function of the FLT1 receptor using genetic means or the drug axitinib, the PARP inhibitors began to work again, killing tumors that were resistant to PARP inhibitors. The researchers said that human breast cancer is likely to develop resistance in the same way. The study found that patients with higher levels of FLT1 in their bodies had a lower success rate with PARP inhibitors because the cancer cells quickly developed resistance. Combining axitinib with a PARP inhibitor may make resistant cancers more responsive to therapy, or even be effective in patients who may not respond to PARP inhibitors from the beginning. The researchers added that since axitinib has been approved by the FDA, the results of this study may be tested in patients soon. The researchers are currently collaborating with multiple research institutions to further study.
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High levels of FLT1 are also present in patients with ovarian cancer, prostate cancer, and pancreatic cancer treated with PARP inhibitors. This may indicate that the same drug combination may be used to treat other types of cancer besides breast cancer. In summary, the results of this study identify FLT1 as a new potential therapeutic target for treating BRCA1/2 mutant breast cancer patients who are resistant to PARP inhibitors.
Reference
Tai Y, et al. FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer. EMBO Molecular Medicine, 2024, 16(8): 1957-1980.