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Mar 21, 2012

Chk1 Inhibition Boosts Chemotherapy in p53-Mutated Triple-Negative Breast Cancer

  • The anticancer effects of irinotecan chemotherapy on specific forms of triple-negative breast cancer (TNBC) can be significantly heightened by the addition of a targeted checkpoint kinase 1 (Chk1) inhibitor, scientists claim. A team led by researchers at Washington University School of Medicine’s Bright Institute has shown p53-mutated human TNBC tumors in mice respond significantly better to irinotecan therapy when the DNA-damaging chemotherapy is combined with a Chk1 inhibitor because the cancer cells are triggered to undergo apoptosis rather than cell cycle arrest.

    Importantly, the results demonstrated that the combined therapy significantly extended the survival of mice with p53-deficient TNBCs, but not those with normal p53-carrying TNBC. Knocking out p53 in TNBC tumors also sensitized these cancers to the combination therapy. Helen Piwnica-Worms, M.D., and colleagues report their findings in the Journal of Clinical Investigation, in a paper titled “Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models.” They claim the effectiveness of their dual therapy in the mouse model indicates that “clinical trials testing this type of strategy in human breast cancer are warranted.”

    TNBC lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) gene amplification, and has a particularly poor prognosis. Importantly, about 44% of TNBCs also demonstrate loss of or mutations in p53, the researchers explain. The tumor suppressor protein p53 normally plays a role in ensuring that cells demonstrating DNA damage arrest at the G1 phase of the cell cycle until the DNA is repaired. However, tumor cells lacking functional p53 rely on Chk1 to stop cell cycle progression in the S and G2 phases in response to DNA damage such as chemotherapy or radiotherapy. In the absence of both p53 and Chk1, damaged cells will instead progress to apoptosis.

    Chk1 inhibitors are already being tested in clinical trials in patients with p53-mutated tumors, and the Bright Institute team predicted that inhibition of Chk1 could enhance the effects of irinotecan selectively in p53-mutated TNBC. They generated human-in-mouse (HIM) models in which p53-mutated or nonmutated patient TMBC explants were immediately engrafted into the humanized mammary fat pads of immunocompromised mice. Such models are particularly useful because they very closely resemble their human tumor counterparts in terms of gene-expression pattern and spectrum of genomic mutations.

    The team tested the effects of combining irinotecan chemotherapy with one of two Chk1 inhibitors, UCN-01 (a nonselective Chk1 and Chk2 inhibitor) or AZD7762 (a selective Chk1 inhibitor). The results clearly demonstrated that Chk1 inhibitors significantly increased the apoptosis-inducing effects of irinotecan, but only in the mutant p53 tumors. Effectively, the investigators state, the irinotecan therapy caused double-stranded breaks (DSBs) in the cells’ DNA, and inhibition of Chk1 prevented the cells from arresting as a result, but enabled them to continue into mitosis, leading to mitotic catastrophe and apoptosis. The overall effect was to significantly reduce the growth of p53 mutant tumors and increase mouse survival times.

    As confirmation that the results weren’t due to other genetic differences between the TNBC tumors in the HIM mice, the experiments were repeated in vitro, in isogenically matched cell lines that differed only in their p53 status. Again, Chk1 inhibition markedly improved the ability of irinotecan to kill p53-deficient cancer cells, and not those carrying normal p53. The effects were similar when either carboplatin or gemcitabine was used in place of irinotecan. And in mice bearing isogenic p53 wild-type, or p53 knockdown breast cancer tumors, irinotecan followed by AZD7762 significantly increased apoptosis in the p53-deficient tumor cells, but not those carrying wild-type p53.

    “Our experiments using HIM TNBC xenograft models provide proof of principle that TNBCs harboring p53 gene mutations may be effectively targeted by the combination of a DNA-damaging agent followed by a Chk1 inhibitor,” the authors conclude. “This synthetic lethal strategy is based on a tumor-specific mutation (the p53 gene mutation) and a drug, in this case a DNA-damaging agent combined with a Chk1 inhibitor, acting together to cause the tumor cell to undergo apoptosis, similar to the synthetic lethal interactions of BRCA1 mutations and poly(ADP-ribose) polymerase (PARP) inhibitor…Several other selective Chk1 inhibitors are in preclinical and clinical development and should provide exciting new opportunities for targeting p53 gene mutant tumors, including a significant fraction of breast cancer.”


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