Abstract
PurposeMost HER2 positive invasive cancers are either intrinsic non-responsive or develop resistance when treated with 1st line HER2 targeting drugs. Both 1st and 2nd line treatments of HER2 positive cancers are aimed at targeting the HER2 receptor directly, thereby strongly limiting the treatment options of HER2/ErbB2 inhibition resistant invasive cancers.MethodsWe used phenotypic high throughput microscopy screening to identify efficient inhibitors of ErbB2-induced invasion using 1st line HER2 inhibitor trastuzumab- and pertuzumab-resistant, p95-ErbB2 expressing breast cancer cells in conjunction with the Prestwick Chemical Library®. The screening entailed a drug’s ability to inhibit ErbB2-induced, invasion-promoting positioning of lysosomes at the cellular periphery, a phenotype that defines their invasiveness. In addition, we used high throughput microscopy and biochemical assays to assess the effects of the drugs on lysosomal membrane permeabilization (LMP) and autophagy, two features connected to cancer treatment. Using 2nd line HER2 inhibitor lapatinib resistant 3-dimensional model systems, we assessed the effects of the drugs on ErbB2 positive breast cancer spheroids and developed a high-throughput invasion assay for HER2 positive ovarian cancer organoids for further evaluation.ResultsWe identified Auranofin, Colchicine, Monensin, Niclosamide, Podophyllotoxin, Quinacrine and Thiostrepton as efficient inhibitors of invasive growth of 2nd line HER2 inhibitor lapatinib resistant breast cancer spheroids and ovarian cancer organoids. We classified these drugs into four groups based on their ability to target lysosomes by inducing autophagy and/or LMP, i.e., drugs inducing early LMP, early autophagy with late LMP, late LMP, or neither.ConclusionsOur results indicate that targetable lysosome-engaging cellular pathways downstream of ErbB2 contribute to invasion. They support lysosomal trafficking as an attractive target for therapy aiming at preventing the spreading of cancer cells. Since these drugs additionally possess anti-inflammatory activities, they could serve as multipurpose drugs simultaneously targeting infection/inflammation and cancer spreading.
Highlights
Breast cancer is the second most common cause for cancer mortality in women
The seven compounds identified are very divergent. When comparing their ability to induce lysosomal membrane permeabilization (LMP) and to modulate autophagy, we found out that the drugs could be roughly divided into four groups, i.e., those (1) inducing early LMP (LMP puncta detection by 12 h; Auranofin and Quinacrine), (2) inducing early autophagy with late LMP (LMP by 48 h; Monensin and Niclosamide), (3) not inducing autophagy with late LMP (Thiostrepton and lapatinib) and (4) not inducing autophagy nor LMP (Colchicine and Podophyllotoxin)
Since Rapamycin is known to induce autophagy, and Concanavalin A (ConA) treatment often leads to inhibition of autophagy, our results suggest that Monensin and Niclosamide treatment initially induced autophagy, perhaps as a survival mechanism, but led to its inhibition and cell death at later timepoints
Summary
Its lethality is caused by highly invasive, metastatic and treatment-resistant cancer cells. HER2/ErbB2 positive breast cancer represents about 20 % of invasive breast cancers. The majority of HER2 positive, advanced invasive breast cancers treated with 1st line HER2 targeting therapy (trastuzumab and/or pertuzumab) together with chemotherapy are either initially non-responsive or develop resistant disease [1,2,3]. The existing treatments against relapsed HER2 positive breast cancer (e.g., TDM1 and lapatinib) are, as the 1st line treatment modalities trastuzumab and pertuzumab, directly targeting HER2. Since resistance towards HER2 targeting can be expected [4, 5], and since the major challenge in HER2 positive cancer is its highly invasive nature, an alternative approach would be to develop therapies that target the invasionpromoting functions of HER2/ErbB2
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