Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease. Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression. To overcome this disease, many investigators attempted to solve the problem of BRAF-inhibitor resistance leading to medically ineffective treatment.
Sensitive and resistance to BRAF inhibition in melanoma
A research indicates that the root of resistance to BRAF inhibitors may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors in many cases. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine (HCQ), and the BRAF inhibitors will be able to do their job better.
Another research interprets why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’. According to analysis, 6 out of 16 melanoma tumours acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Suppression of sex determining region Y-box 10 (SOX10) in melanoma is found to cause activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. Additionally, investigators find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples.
With the application of value, Moffitt researchers found that using two inhibitors (Mekinist [trametinib] and Tafinlar[dabrafenib]) to block different growth pathways during treatment prevented resistance in patients with BRAF mutation. The combination of these two inhibitors, as a newly FDA-approved therapy, is one of the biggest advancements in melanoma treatment in the past 30 years. From a clinical perspective, 76 percent of patients achieve success in the treatment of the Mekinist and Tafinlar combination, and this therapy reduces the incidence and severity of some of the toxic effects patients experience when the drugs is used alone.
1. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014 Apr 3;508(7494):118-22.
2. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. New England Journal of Medicine, 2012; 367 (18): 1694 DOI: 10.1056/NEJMoa1210093
3. Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI70454
Some patients with metastatic lung ,colorectal or pancreatic cancers initially show positive results from EGFP-targeted therapies, however the resistance to targeted therapies eventually develops. In order to make it effective, researchers attempt to understand what related proteins in a signaling network cause resistance of tumors to EGFR inhibitors. With growing knowledge of resistance pathways appear, we obtain a great chance to develop new mechanism-based inhibitors or joint therapies to prevent therapeutic resistance in tumors.
Louis Weiner et al discuss how cancer cells activate a network of specific proteins which evade a molecule from being therapeutically in the issue of Science Signal. Treatment by FDA-approved drugs that are designated to shut down the EGFR tend to be inefficient, partly due to involving of some genes in evading cancer cells. He says the essence of drug resistance is evolutionary pressure to survive, and the only way to treat cancer is to disarm some of key “rescue” genes and proteins. by using a screen technique, investigators identified 61 genes that play some role in anti-EGFR drug resistance.
The concept of oncogene addiction was defined by Weinstein in 2002, which highlights the crucial importance of EGFR to tumor cell survival in lung adenocarcinoma. It means that a cancer cell is dependent of a specific oncogenic signaling pathway. For instance. Drugs that inhibit mutant EGFR such as erlotinib turn off this key pathway and result in tumor cell apoptosis.
A decade later, oncogene-targeted therapies grant a reprieve for patients who are lucky to have been selected driver mutation, and alleviation last years in some cases. For patients with EGFR-mutant lung cancer, tumor responses persist for months which is better than patients without such a mutation.
Cancer researchers and clinicians should realize the importance of perseverance, creativity and collaboration. Whether tumor resistance is defeated using combinations of drugs, immunotherapy, new dosing strategies or an undiscovered approach, patients cannot benefit from novel therapies soon enough.
Treatments may be used not only to treat and to control the myeloma itself, but also to ease symptoms and complications of the myeloma. Radiotherapy, Bisphosphonates, and Other Supportive Therapies would bring about adverse effects, Such as bone pain and fractures. Thus, developing effective therapies against multiple myeloma (MM) is a pending challenge.
PI3K activation may be correlated with tumor progression and drug resistance, and inhibiting PI3K can induce apoptosis in MM cells. Therefore, inactivation of PI3K is predicted to increase the susceptibility of MM to anticancer therapy. Glauer J, et al demonstrated that a novel class of PI3K inhibitors, BAY80-6946, was highly efficacious in four different MM cell lines, where it induced significant antitumoral effects in a dose-dependent manner. The compound inhibited cell cycle progression and increased apoptosis, and showed convincing in vivo activity against the human AMO-1 and MOLP-8 myeloma cell lines in a preclinical murine model.
Additionally, Munugalavadla V et al indicated that the PI3K inhibitor GDC-0941, combined with existing clinical regimens, exhibited superior activity in multiple myeloma. In vitro, GDC-0941 was synergized with dexamethasone and lenalidomide; in vivo GDC-0941 had anti-myeloma activity and significantly increased the activity of the standard of care agents in several murine tumor models.
These data provide a clear therapeutic prospect for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.
Previously study has been shown that, α-catenin could complex with the IκBα protein, and stabilize IκBα by inhibiting its and its association with the proteasome.
Usually, Aberrant activation of NF-κB signaling is found in triple-negative basal-like breast cancer cells, while the cause of this activation has remained elusive，The NF-κB pathway can be activated by a variety of factors. Activated NF-κB regulates kinds of target genes. Aberrant activation of NF-κB signaling is associated with various human cancers including breast cancer.
Researchers from Texas MD Anderson Cancer Center discovered that, loss of α-catenin as a mechanism by which the NF-kB pathway is activated in the basal-like subtype of breast cancer. This is highly relevant in human tumors, as alpha-catenin is specifically downregulated in human basal-like breast cancer, correlates with recurrence-free survival and negatively correlates with the activity of NF-κB signalling. Thus, Targeting the NF-κB pathway may provide therapeutic benefits to patients with basal-like, triple-negative breast cancer
Reference: alpha-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling. Nature cell biology, 2014