Advances in immunotherapy for MMR proficient colorectal cancer.

Survival in mismatch-repair proficient (MMRp) metastatic colorectal cancer (mCRC) remains poor and chemotherapy is the mainstay of treatment. Immunotherapy has demonstrated durable responses and a favourable side-effect profile in various cancer types and multiple clinical trials have been conducted in MMRp mCRC. In this review we summarise emerging trial data which demonstrate promising immunotherapy combinations in MMRp mCRC. We outline barriers to success, evaluate emerging biomarkers and discuss potential strategies to increase the effectiveness of immunotherapy in MMRp mCRC

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma

SC was funded by fellowships from NIHR and Cancer Research UK. IK was funded by the UCLH Experimental Cancer Centre and UCLH NIHR Biomedical Research Centre. TP was funded by grants from Cancer Research UK (the Experimental Cancer Medicine Centre). MG was funded by grants from Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, the Schottlander Research Charitable Trust, the Royal Marsden NIHR Biomedical Research Centre for Cancer and the Wellcome Trust (grant number: 105104/Z/14/Z

Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

BACKGROUND: In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance. METHODS: To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome reprogramming in an established cellular model of acquired, KRAS-associated CET resistance. RESULTS: This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly, all investigated resistant cell lines displayed upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of traits of progression. Expectedly resistant cell lines displayed increased migration (p < 0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (RNAi) (p < 0.001), ephrin-A1 stimulation (p < 0.001), dasatinib (p < 0.01), or anti-EPHA2 antibody treatment (p < 0.001), identifying it as an actionable target in mCRC with acquired CET resistance. CONCLUSION: These results highlight EPHA2 and its role in mCRC with KRAS-gene mutated acquired CET resistance and support its use as a potential actionable target for the development of future precision medicine therapies