RESUMEN
Gastric cancer (GC) is the second leading cause of cancer-related death world-wide. Despite improvements in prevention, early detection and various therapeutic options, the prognosis is still poor. GC is often diagnosed at an advanced stage with survivals less than 1 year. Chemotherapy as the mainstay of treatment in advanced stage is not of notable advantages, underlining the need for novel more effective therapeutic options. Based on current knowledge of molecular and cellular mechanisms, a number of novel biologic approaches such as monoclonal antibodies have been recently introduced for cancer treatment that mainly affect the immune system or target signaling pathways playing role in cancer and metastasis development. In this review, various monoclonal antibodies for GC therapy were explained.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/tendencias , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Gástricas/terapia , Animales , Antígeno B7-H1/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Progresión de la Enfermedad , Humanos , Estadificación de Neoplasias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Gástricas/inmunologíaRESUMEN
BACKGROUND: To evaluate the association between fatigue and anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MAbs), we conducted the first meta-analysis to access the incidence and risk of fatigue associated with anti-EGFR MAbs. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) published up to February 2017. Eligible studies were selected according to PRISMA statement. Incidence rates, risk ratio (RRs), and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Outcomes of quality were summarized in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. RESULTS: Thirty-five RCTs (including 15,622 patients) were included; median follow-up ranged from 8.1 to 71.4 months, and the fatigue events were recorded and graded according to the Common Toxicity Criteria for Adverse Events version 2.0 or 3.0 in most of the included trials. For patients receiving anti-EGFR MAbs, the overall incidence of all-grade and high-grade fatigue was 54.1% and 10.5%, respectively. Compared with control, anti-EGFR MAbs significantly increased the risk of all-grade fatigue (RR 1.10, 95% CI, 1.05-1.14, moderate-quality evidence) and high-grade fatigue (RR 1.31, 95% CI, 1.19-1.45, moderate-quality evidence). No significant differences among subgroup analyses (anti-EGFR MAbs, tumor type, and median follow-up) on high-grade fatigue were observed. No evidence of publication bias was observed. CONCLUSION: The present study suggested that anti-EGFR MAbs may increase the risk of fatigue in cancer patients.
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Antineoplásicos/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Fatiga/inducido químicamente , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/uso terapéutico , Cetuximab/efectos adversos , Humanos , Panitumumab , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Barely 10-20% of patients with metastatic colorectal cancer (mCRC) receive a clinical benefit from the use of anti-EGFR monoclonal antibodies (mAbs). We hypothesized that this could depends on their efficiency to reduce Store Operated Calcium Entry (SOCE) that are known to enhance cancer cells. RESULTS: In the present study, we demonstrate that SOCE promotes migration of colon cancer cell following the formation of a lipid raft ion channel complex composed of TRPC1/Orai1 and SK3 channels. Formation of this complex is stimulated by the phosphorylation of the reticular protein STIM1 by EGF and activation of the Akt pathway. Our data show that, in a positive feedback loop SOCE activates both Akt pathway and SK3 channel activity which lead to SOCE amplification. This amplification occurs through the activation of Rac1/Calpain mediated by Akt. We also show that Anti-EGFR mAbs can modulate SOCE and cancer cell migration through the Akt pathway. Interestingly, the alkyl-lipid Ohmline, which we previously showed to be an inhibitor of SK3 channel, can dissociated the lipid raft ion channel complex through decreased phosphorylation of Akt and modulation of mAbs action. CONCLUSIONS: This study demonstrates that the inhibition of the SOCE-dependent colon cancer cell migration trough SK3/TRPC1/Orai1 channel complex by the alkyl-lipid Ohmline may be a novel strategy to modulate Anti-EGFR mAb action in mCRC.
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Calcio/metabolismo , Movimiento Celular/fisiología , Proteína ORAI1/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Canales Catiónicos TRPC/metabolismo , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Movimiento Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Glucolípidos/farmacología , Células HCT116 , Humanos , Immunoblotting , Microdominios de Membrana/metabolismo , Complejos Multiproteicos/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
INTRODUCTION: KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA). PATIENTS AND METHODS: Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS (wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations. RESULTS: Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004). CONCLUSION: Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.