KRAS mutations are one of the most frequent oncogenic mutations of all human cancers, being more prevalent in pancreatic, colorectal, and lung cancers. Intensive efforts have been encouraged in order to understand the effect of KRAS mutations, not only on tumor cells but also on the dynamic network composed by the tumor microenvironment (TME). The relevance of the TME in cancer biology has been increasing due to its impact on the modulation of cancer cell activities, which can dictate the success of tumor progression. Here, we aimed to clarify the pro- and anti-inflammatory role of KRAS mutations over the TME, detailing the context and the signaling pathways involved. In this review, we expect to open new avenues for investigating the potential of KRAS mutations on inflammatory TME modulation, opening a different vision of therapeutic combined approaches to overcome KRAS-associated therapy inefficacy and resistance in cancer.

KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations.

Background The platelet-to-lymphocyte ratio (PLR) index has recently been a focus of investigation as a reliable marker of inflammation, being shown to have a good accuracy upon predicting endoscopic remission in patients with colonic Crohn’s Disease (CD). We aimed to evaluate and validate the discriminative power of PLR index in patients with small bowel CD. Methods Single center study including patients with isolated small bowel CD (L1 ± L4 disease according to Montreal classification) undergoing small bowel capsule endoscopy (SBCE) for assessment of endoscopic activity. CD endoscopic activity was classified according to the Lewis score (LS) value. Complete blood count, C-reactive protein and fecal calprotectin values were collected within 1 month of SBCE. A retrospective sample was used for initial assessment of PLR index performance, followed by a prospective 2-years application on a distinct sample. Results The initial sample included 49 and the validation sample 48 patients, both groups being age- and gender-matched. On the initial cohort, PLR index presented a positive moderate correlation with LS (k=0.597; p<0.001), which was stronger than the one found with fecal calprotectin (k=0.525; p=0.001) or C-reactive protein (k=0.321; p=0.029). PLR index presented an excellent accuracy for predicting patients with a moderate-to-severe endoscopic activity (AUC=0.91; 95%CI=0.82-0.99; p<0.001), and a good accuracy for prediction of mucosal healing (AUC=0.74; 95%CI=0.60-0.89; p=0.007). These results were confirmed on the prospective validation cohort, as the correlation of LS with PLR index (k=0.631; p<0.001) was further stronger than with fecal calprotectin (k=0.355; p=0.040) and C-reactive protein (k=0.183; p=0.219). The accuracy of PLR index was confirmed to be excellent for moderate-to-severe endoscopic activity (AUC=0.87; 95%CI=0.76-0.98; p<0.001) and good for mucosal healing (AUC=0.74; 95%CI=0.59-0.87; p<0.001). Conclusion PLR index demonstrated an excellent acuity in predicting moderate-to-severe disease and good acuity in predicting mucosal healing in patients with small bowel CD, with both associations confirmed on a prospective validation cohort. Our findings establish this index as a promising and easy-to-apply tool for non-invasive and regular follow-up of patients with small bowel CD.

Background Contrary to the Simple Endoscopic Score for Crohn’s Disease (SES-CD), Modified Multiplier SES-CD (MM-SES-CD) is a new endoscopic severity assessment tool that was able to predict one-year endoscopic remission in patients with Crohn’s Disease (CD) on active therapy. Unlike SES-CD, MM-SES-CD accounts for the number of segments affected and the different prognostic weight of individual SES-CD parameters according to disease location. Nevertheless, there is scarce information regarding its relationship with laboratorial parameters, namely C-reactive protein (CRP) and fecal calprotectin (FC). We aimed to analyze the association between MM-SES-CD and these laboratorial parameters. Methods Retrospective cohort-study including all ileocolonoscopies performed in adult CD patients between January 2020 and October 2022 with CRP (mg/dL) and FC (ug/g) collected within one month. Patients with previous intestinal surgery or inadequate bowel preparation were excluded. MM-SES-CD, ranging from 0 to 130.5, was calculated and different severity categories were defined as follows: remission (<14), mild (≥14 to <31), moderate (≥31 to <45), and severe (≥45). MM-SES-CD values were correlated and compared, according to severity categories, with laboratorial biomarkers. Results A total of 272 ileocolonoscopies from 218 CD patients were included, most females (54.1%) with a mean age of 41 years old. Most patients were A2 (72.8%), L1 (51.1%) and B1 (73.9%), according to Montreal classification. Median MM-SES-CD, CRP and FC was 12.0, 2.9 and 222.0, respectively. Despite MM-SES-CD values correlated weakly with CRP (r=0.376, P<0.001) and moderately with FC (r=0.531, P<0.001), patients with endoscopic remission had significantly lower median CRP (2.9 vs 7.7, P<0.001) and FC (128 vs 587, P<0.001) than patients with active disease. Additionally, median CRP (2.9 vs 6.0 vs 16.0 vs 30.7, P<0.001), and median FC (128 vs 531 vs 637 vs 877, P<0.001) were significantly different between MM-SES-CD severity categories (remission vs mild vs moderate vs severe), respectively. CRP and FC optimal cut-offs for endoscopic remission were 8.5 mg/dL (Sensitivity 74.7%, Specificity 43.6%, negative predictive value (NPV) 77.4%, positive predictive value (PPV) 40.0%) and 471.5 ug/g (Sensitivity 62.6%, Specificity 87.3%, NPV 82.3%, PPV 71.3%), respectively. Conclusion To the best of our knowledge, this is the first study reporting an association between CRP and FC and increasing degrees of disease activity assessed by MM-SES-CD. A CRP <8.5 mg/dL and a FC <471.5 ug/g are suggested as cut-offs associated with endoscopic remission.