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Science. cell lines express on average 11 druggable mutations, including frequent mutations ( 20%) in the receptor tyrosine kinases AXL and EPHA2, which have not been previously considered as potential targets for colorectal cancer. Finally, we identified 82 cell surface mutated epitopes, however expression of only 30% of these epitopes was detected in our cell lines. Notwithstanding, 92% of these epitopes were expressed in cell lines with the mutator phenotype, opening new venues for the use of general immune checkpoint drugs in this subset of patients. propagation of the cell lines, our results are in agreement with a recent mutation saturation analysis of 4,742 sequenced tumors, across 21 cancer types [6]. This study revealed that this discovery of cancer genes mutated at frequencies of 5C10% in colorectal tumors is usually increasing linearly in relation to the number of tumor genomes sequenced, and that the current collection of sequenced colorectal tumors lacks the desired power to detect genes mutated at frequencies of 5% above the background rate [6]. SEMA4C mutations were found in 17% of the cell lines and recurrent mutations in SEMA4G (17%) and SEMA4D (22%) were also observed. The effects of Semaphorins and their receptors in cancer are broad, context dependent and complex [37]. SEMA4C is usually Lithospermoside expressed in neural stem cells and its expression is usually downregulated during stem cell differentiation [14]. SEMA4C expression is usually induced by TGF-1 Lithospermoside in renal epithelial cells and plays and important role in TGF-1 induced epithelial-mesenchymal transition [15]. In addition, an important role of SEMA4D-Plexin-B1 conversation in regulating different aspects leading to tumor progression, including invasive growth and angiogenesis, is usually well established [16]. The pro-angiogenic effect of SEMA4D was exhibited both and and is comparable to that elicited by other well-known angiogenic molecules, such as VEGF-A, HGF and bFGF [38, 39]. Our results suggest that SEMA4 signaling is usually activated by point mutations in a significant fraction of colorectal tumors, and although specific inhibitors targeting SEMA4 proteins are not currently available, several Lithospermoside biological process driven by SEMA4 signaling, such as angiogenesis and invasiveness, could be targeted with FDA approved drugs, including anti-angiogenic brokers and MET inhibitors. Inactivating mutations in FGFRL1, the most Lithospermoside recently discovered member of the FGFR family, were detected in 17% of our cell lines. FGFRL1 binds with high affinity to heparin and FGF ligands, but it does not possess an intracellular protein kinase domain name and, therefore, cannot signal by trans-auto-phosphorylation [18]. FGFRL1 thus acts as a negative regulator of FGFR1 signaling and loss of function mutations described here may represent a novel mechanism of FGF signaling activation in colorectal cancer. Alterations in FGFR1, FGFR2 and FGFR3 were also observed at a lower frequency, and 35% of the cell lines harbored somatic mutations in members of the FGF signaling pathway. Different FGFR specific inhibitors are currently under development [40], and further evaluation of their activity in the subset of colorectal cancer with FGFR/FGFRL1 alterations should be pursued. Moreover, Regorafenib, a multi-kinase inhibitor that targets FGFR1 among other RTKs, was recently approved by the FDA for the treatment of advanced colorectal cancer [41], but predictive biomarkers for this indication are not yet currently available. Higher mutation frequencies in the RTKs AXL (22%) and EPHA2 (17%) were detected in our panel compared to those reported in the TCGA database for primary colorectal tumors (3.51% AXL and 2.63% EPHA2) [5]. Both RTKs have not been considered as potential therapeutic targets for colorectal cancer, however the availability of specific inhibitors and pre-clinical data support their potential use for therapeutic intervention. The oncogenic properties of AXL were initially described in patients with chronic myelogenous and lymphoblastic leukemia (CML), but overexpression of AXL have also been detected in many solid tumors and associated with poor prognosis [23]. AXL has a well established oncogenic role in survival, Lithospermoside proliferation and migration of cancer cells [23]. Moreover, recent studies have uncovered a major role of AXL IKBKB in primary and acquired resistance to several anticancer therapies. AXL overexpression has been linked to Imatinib-resistance in gastrointestinal stromal tumors [42], Nilotinib-resistance in CML [43] and Lapatinib-resistance in HER-2 positive breast tumor cells [44]. In lung cancer, AXL was identified as a potential target for overcoming EGFR inhibitor resistance and combination of an AXL specific inhibitor (SGI-7079) with Erlotinib reversed Erlotinib resistance in a xenograft model of mesenchymal non-small cell lung cancer [45]. In colorectal cancer, AXL expression is usually.