SummaryFocal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8+ T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8+ T cell activity, permitting growth of FAK-expressing tumors. Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Furthermore, FAK’s immuno-modulatory nuclear activities may be specific to cancerous squamous epithelial cells, as normal keratinocytes do not have nuclear FAK. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8+ T cell-mediated anti-tumor response. Therefore, FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic opportunities.

Metastasis is the spread of cancer cells from a primary tumor to distant sites within the body to establish secondary tumors. Although this is an inefficient process, the consequences are devastating as metastatic disease accounts for >90% of cancer-related deaths. The formation of metastases is the result of a series of events that allow cancer cells to escape from the primary site, survive in the lymphatic system or blood vessels, extravasate and grow at distant sites. The metastatic capacity of a tumor is determined by genetic and epigenetic changes within the cancer cells as well as contributions from cells in the tumor microenvironment. Mouse models have proven to be an important tool for unraveling the complex interactions involved in the metastatic cascade and delineating its many stages. Here, we critically appraise the strengths and weaknesses of the current mouse models and highlight the recent advances that have been made using these models in our understanding of metastasis. We also discuss the use of these models for testing potential therapies and the challenges associated with the translation of these findings into the provision of new and effective treatments for cancer patients.

Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular carcinoma (ILC), options to treat this major breast cancer subtype are limited if tumours develop resistance to anti-oestrogen treatment regimens. This study aimed to identify clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Using a combination of reverse-phase protein array (RPPA) analyses, mRNA sequencing, conditioned medium growth assays and CRISPR/Cas9-based knock-out experiments, we demonstrate that E-cadherin loss causes increased responsiveness to autocrine growth factor receptor (GFR)-dependent activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signalling. Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN. Analyses of human ILC samples confirmed growth factor production and pathway activity. Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model. Because E-cadherin loss evokes hypersensitisation of PI3K/Akt activation independent of oncogenic mutations in this pathway, we propose clinical intervention of PI3K/Akt in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.

Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies in the treatment of HER2-positive breast cancer is a major clinical problem. To identify pathways linked to resistance, we generated HER2-positive breast cancer cell lines which are resistant to either lapatinib or AZD8931, two pan-HER family kinase inhibitors. Resistance was HER2 independent and was associated with epithelial-to-mesenchymal transition (EMT), resulting in increased proliferation and migration of the resistant cells. Using a global proteomics approach, we identified a novel set of EMT-associated proteins linked to HER2-independent resistance. We demonstrate that a subset of these EMT-associated genes is predictive of prognosis within the ERBB2 subtype of human breast cancers. Furthermore, targeting the EMT-associated kinases Src and Axl potently inhibited proliferation of the resistant cells, and inhibitors to these kinases may provide additional options for the treatment of HER2-independent resistance in tumors.

Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies presents a major clinical problem. Although preclinical studies have identified a number of possible mechanisms, clinical validation has been difficult. This is most likely to reflect the reliance on cell-line models that do not recapitulate the complexity and heterogeneity seen in human tumours. Here, we show the utility of a genetically engineered mouse model of HER2-driven breast cancer (MMTV-NIC) to define mechanisms of resistance to the pan-HER family inhibitor AZD8931. Genetic manipulation of MMTV-NIC mice demonstrated that loss of phosphatase and tensin homologue (PTEN) conferred de novo resistance to AZD8931, and a tumour fragment transplantation model was established to assess mechanisms of acquired resistance. Using this approach, 50% of tumours developed resistance to AZD8931. Analysis of the resistant tumours showed two distinct patterns of resistance: tumours in which reduced membranous HER2 expression was associated with an epithelial-to-mesenchymal transition (EMT) and resistant tumours that retained HER2 expression and an epithelial morphology. The plasticity of the EMT phenotype was demonstrated upon re-implantation of resistant tumours that then showed a mixed epithelial and mesenchymal phenotype. Further AZD8931 treatment resulted in the generation of secondary resistant tumours that again had either undergone EMT or retained their original epithelial morphology. The data provide a strong rationale for basing therapeutic decisions on the biology of the individual resistant tumour, which can be very different from that of the primary tumour and will be specific to individual patients.