Therapy-induced senescence (TIS) is considered a permanent cell cycle arrest following DNA-damaging treatments; however, its irreversibility has recently been challenged. Here, we demonstrate that escape from TIS is universal across breast cancer cells. Moreover, TIS provides a reversible drug resistance mechanism that ensures the survival of the population, and could contribute to relapse. TIS was induced in four different breast cancer cell line with high-dose chemotherapy and cultured until cells escaped TIS. Parental, TIS and repopulating cells were analyzed by bulk and single-cell RNA sequencing and surface proteomics. A genetically engineered mouse model of triple-negative breast cancer was used to prove why current senolytics cannot overcome TIS in tumors. Screening the toxicity of a diverse panel of FDA-approved anticancer drugs revealed that TIS meditates resistance to half of these compounds, despite their distinct mechanism of action. Bulk and single-cell RNA sequencing, along with surface proteome analysis, showed that while parental and repopulating cells are almost identical, TIS cells are significantly different from both, highlighting their transient nature. Furthermore, investigating dozens of known drug resistance mechanisms offered no explanation for this unique drug resistance pattern. Additionally, TIS cells expressed a gene set associated with immune evasion and a potential KRAS-driven escape mechanism from TIS. Our results reveal that TIS, as a transient drug resistance mechanism, could contribute to overcome the immune response and to relapse by reverting to a proliferative stage.

Chemotherapy optimization based on mathematical models is a promising direction of personalized medicine. Personalizing, thus optimizing treatments, may have multiple advantages, from fewer side effects to lower costs. However, personalization is a complicated process in practice. We discuss a mathematical model of tumor growth and therapy optimization algorithms that can be used to personalize therapies. The therapy generation is based on the concept of keeping the drug level over a specified value. A mixed-effect model is used for parametric identification, and the doses are calculated using a two-compartment model for drug pharmacokinetics, and a nonlinear pharmacodynamics and tumor dynamics model. We propose personalized therapy generation algorithms for having a maximal effect and minimal effective doses. We handle inter- and intra-patient variability for the minimal effective dose therapy. Results from mouse experiments for the personalized therapy are discussed and the algorithms are compared to a generic protocol based on overall survival. The experimental results show that the introduced algorithms significantly increased the overall survival of the mice, demonstrating that by control engineering methods an efficient modality of cancer therapy may be possible.

We synthesized substituted benzaldehyde derived α-hydroxyphosphonates (αOHP), α-hydroxyphosphonic acids (αOHPA) and α-phosphinoyloxyphosphonates (αOPP) and characterized their cytotoxicity against a panel of cancer cell lines.

Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this study, the function of Tks4 was investigated in HCT116 colon cancer cells by knocking the protein out using the CRISPR/Cas9 system. Surprisingly, the absence of Tks4 induced significant changes in cell morphology, motility, adhesion and expression, and localization of E-cadherin, which are all considered as hallmarks of EMT. In agreement with these findings, the marked appearance of fibronectin, a marker of the mesenchymal phenotype, was also observed in Tks4-KO cells. Analysis of the expression of well-known EMT transcription factors revealed that Snail2 was strongly overexpressed in cells lacking Tks4. Tks4-KO cells showed increased motility and decreased cell–cell attachment. Collagen matrix invasion assays demonstrated the abundance of invasive solitary cells. Finally, the reintroduction of Tks4 protein in the Tks4-KO cells restored the expression levels of relevant key transcription factors, suggesting that the Tks4 scaffold protein has a specific and novel role in EMT regulation and cancer progression.

Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. By the age of 80, the estimated risk for breast cancer for women with germline BRCA1 or BRCA2 mutations is around 80%. Genetically engineered BRCA1-deficient mouse models offer a unique opportunity to study the pathogenesis and therapy of triple negative breast cancer. Here we present a newly established Brca1^−/−, p53^−/− mouse mammary tumor cell line, designated as CST. CST shows prominent features of BRCA1-mutated triple-negative breast cancers including increased motility, high proliferation rate, genome instability and sensitivity to platinum chemotherapy and PARP inhibitors (olaparib, veliparib, rucaparib and talazoparib). Genomic instability of CST cells was confirmed by whole genome sequencing, which also revealed the presence of COSMIC (Catalogue of Somatic Mutations in Cancer) mutation signatures 3 and 8 associated with homologous recombination (HR) deficiency. In vitro sensitivity of CST cells was tested against 11 chemotherapy agents. Tumors derived from orthotopically injected CST-mCherry cells in FVB-GFP mice showed sensitivity to cisplatin, providing a new model to study the cooperation of BRCA1-KO, mCherry-positive tumor cells and the GFP-expressing stromal compartment in therapy resistance and metastasis formation. In summary, we have established CST cells as a new model recapitulating major characteristics of BRCA1-negative breast cancers.