The majority of patients with early stage TNBC are treated with neoadjuvant chemotherapy as pre-surgery treatment. Treatment of TNBCs depends on chemotherapy, due to the lack of specifically approved targeted therapies.
This subgroup is more aggressive and is associated with an unfavorable prognosis 2, 3. Triple negative breast cancer (TNBC) accounts for 12–17% (depending on immunohistochemical cut-offs used) of all breast cancer patients and are defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.īreast cancer has the highest estimated incidence rate across all cancers 1. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. The novel toriCAM application is able to significantly improve the accuracy of reference marking for both freehand and slit-lamp methods.Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy.
Comparison of the freehand and slit-lamp methods did not show any statistically significant difference in accuracy at both time points.
This improvement was also noted separately in the freehand and slit-lamp groups. This was significantly reduced to 1.28° ± 1.34° after using the application (P <. The mean absolute error of all markings before toriCAM adjustment was 3.18° ± 2.22°. Twenty eyes of 11 patients were marked using the freehand method and 20 eyes of the other 11 patients were marked using the slit-lamp method. The errors in marking with and without using the application were analyzed for all patients in each cohort and determined for each marking method. The toriCAM application on a smartphone was then used to assess the rotational alignment of these markings and compared to the actual alignment as measured by the Zaldivar calipers on the iTrace Topographer (Tracey Technologies, Houston, TX) as a reference. Corneal markings at 0° and 180° were made using either method. In this prospective, randomized study, 22 participants were randomly allocated to two groups, either freehand or slit-lamp-assisted marking. To compare the accuracy of two common reference marking methods for toric intraocular lens alignment before and after using the novel toriCAM application.
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