E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer

Abstract

The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization., ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients. E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin-defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. .

Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

“…Breast cancer metastasis to gynaecological organs Kutasovic et al [45]. We also observed that ILC was more likely to colonise the uterus than IC-NST and, amongst non-GMs, ILC more frequently colonised the GI tract and less frequently the lungs and CNS compared to IC-NST.…”

“…While ILC generally affects older women , patients in the GM cohort were relatively young (median 44 years), suggesting that young age of ILC diagnosis may be a risk factor for GM, and raising the possibility that these women could benefit from closer clinical surveillance. Moreover, ILC patients who relapsed after 5 years were significantly younger than those who relapsed within 5 years, suggesting that these women may be suitable candidates for extended endocrine therapy , addition of palbociclilb , or inclusion in emerging clinical trials specifically for E‐cadherin defective ILC . We also observed that ILC was more likely to colonise the uterus than IC‐NST and, amongst non‐GMs, ILC more frequently colonised the GI tract and less frequently the lungs and CNS compared to IC‐NST.…”

Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

“…5 D). Further, CDH1 knockout MCF-7 cells (Bajrami et al, 2018) engulfed at the same rate as parental MCF-7 cells (Fig. 5, E–G).…”

Single cell transcriptomic heterogeneity in invasive ductal and lobular breast cancer cells

“…ILC is the 6 th most common cancer in women, with an estimated 40,000 new cases in 2019, despite accounting for a smaller proportion of breast cancer cases (~15%) compared to IDC (~75%) 1 . ILC shows distinct signaling in pathways essential for breast cancer growth and proliferation compared to IDCsuch as the WNT4 signaling in response to estrogen stimulus or blockade 2,3 , increased PI3K/Akt signaling 4,5 , enhanced IGF1-IGF1R activation 6 , and dependency on ROS1 7 , which suggest that ILC could benefit from unique treatment strategies. The most distinguishing molecular feature of ILC is loss of E-cadherin, largely arising from inactivating CDH1 mutations.…”