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Therefore, the combination of anti-CD20 and NO donors should result in the inhibition of tumor cell proliferation and the reversal of resistance of B-NHL cells. It is postulated that the combination use of well-designed subtoxic NO donors in combination with anti-CD20 mAbs should result in the improved treatment of patients who are initially unresponsive and/or are refractory to prior treatments.Rituximab, a chimeric mouse/human monoclonal antibody (mAb) targeting CD20, has proven to improve treatment outcomes in a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Rituximab in combination with standard chemotherapeutic regimens (R-CHOP) has proven to be the current standard treatment, with successful outcomes in a larger subset of patients compared to monotherapy. However, in addition to initially nonresponding patients, evidence suggests that many responding patients develop resistance to further treatments. The mechanisms by which monoclonal antibodies target CD20 in vivo are poorly understood, although the implicated mechanisms include the direct induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). The processes of other postulated mechanisms considered to be intracellular antitumor effects are also described in this review. Here we discuss methods for reversing resistance to anti-CD20 antibody therapies via targeting intracellular signaling pathways that regulate resistant factors. With an increased understanding of the underlying mechanisms of resistance, more effective new approaches may be developed for early diagnosis and therapeutic responses.CD20-targeting antibodies are the current standard of care for patients with mature B-cell malignancies. However, many patients relapse or develop therapy resistance, which emphasizes the urgent need for new therapies. Here, we provide an overview of the biology of the CD20 protein and the mechanisms of action of CD20 antibodies currently used in the clinic. In addition, we discuss different mechanisms underlying therapy resistance, and recent advances made in the development of novel antibody-based therapeutics to improve clinical outcome of patients with mature B-cell malignancies.Human epidermal growth factor receptor (HER2) is a well-established histopathological marker. It is aberrantly expressed in various cancers, predominantly in breast cancer. HER2 protein overexpression and/or HER2 gene amplification induces HER2 dimerization, tyrosine kinase (TK) phosphorylation, activation of different signaling pathways including the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and hence, carcinogenesis. HER2 antibodies like trastuzumab and pertuzumab act on the extracellular domain (ECD) of the HER2 receptor. These were developed to treat HER2-overexpressing or amplified cancers. These effectively inhibit HER2 dimerization and, hence, further signaling. However, antibody resistance and, thereby, disease relapse have emerged as serious concerns. HER2 splicing, cross-signaling, and intracellular alterations are the most common factors causing HER2-antibody resistance. To overcome the therapeutic resistance associated with trastuzumab, TK inhibitors (Ttant cancers to HER2 antibodies.Development of HER2-targeted therapy drugs, particularly trastuzumab, demonstrated significant improvement of clinical outcomes among HER2 positive breast cancer patients during the last two decades. The exact biological mechanism of HER2 gene amplification occurrence remains unsolved. HER2 gene amplification and/or HER2 protein overexpression are the primary predictors for selecting invasive breast cancer patients as candidates for anti-HER2 agent-based chemotherapy protocol. However, HER2-targeted therapy is not completely successful as it is well-documented, only one half of HER2 positive breast cancer patients achieve a pathological complete response after such a precision therapy. In the past, various HER2 drug resistance mechanisms were proposed for explaining incomplete the efficacy with anti-HER2 drugs. selleck chemical Recent studies suggested that HER2 intratumoral heterogeneity (ITH) determined by a concomitant HER2 gene and protein analyses are a significant primary resistance mechanism to HER2-targeted therapy. Recent discovery of undocumented "nonclassic" HER2-positive tumor cells with the amplified HER2 gene but no HER2 protein overexpression redefined HER2 ITH. The HER2 ITH consists of two groups of tumor heterogeneity subtypes (1) genetic ITH (a mixture of HER2 negative tumor cells and classic HER2 positive tumor cells) and (2) nongenetic ITH (a mixture of classic HER2 positive tumor cells and nonclassic HER2 positive tumor cells). The mechanism underlining these nonclassic HER2 positive tumor cells with the amplified HER2 gene, but no HER2 protein overexpression, is unknown. Investigation of impaired HER2 and/or protein translation in these tumor cells could lead to a further improvement of cancer therapy by identifying new therapeutic targets for patients with HER2 ITH.The discovery of human epidermal growth factor receptor 2 (HER2) and its role in breast cancer led to the development of the first targeted antibody treatment for HER2-positive breast cancer. This treatment breakthrough led to remarkable improvements in both early and late survival. Unfortunately, not all patients with HER2 breast cancer responded positively; some have innate resistance to treatment and others develop resistance over time. In this review, we discuss some research that is currently underway to understand HER2 resistance and strategies in overcoming it.Human epidermal growth factor receptor 2 (HER2) oncogene addiction has led to the development of anti-HER2 therapies which have revolutionized the management of patients with HER2-positive cancers, with trastuzumab being the cornerstone of treatment of HER2-positive breast cancer. Despite the success of these biologics in breast cancer patients, not all patients with HER2-positive tumors respond to treatment, and many eventually develop resistance to therapy. Developing therapies that that circumvent current resistance mechanisms and improve patient outcomes further remains an area of unmet clinical need. Based on insights gained from established anti-HER2 therapies and our understanding of known resistance mechanisms a number of novel anti-HER2 treatments are being developed. These include novel HER2 antibody-drug conjugates that have shown activity in HER2 high and low tumors, novel HER2 antibodies, T cell bispecific antibodies, and HER2 antibodies in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, immunotherapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.