Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms

Pituitary neuroendocrine tumors (PitNET) are commonly benign tumors accounting for 10-25% of intracranial tumors. Prolactin-secreting adenomas represent the most predominant type of all PitNET and for this subtype of tumors, the medical therapy relies on the use of dopamine agonists (DAs). DAs yield an excellent therapeutic response in reducing tumor size and hormonal secretion targeting the dopamine receptor type 2 (D2DR) whose higher expression in prolactin-secreting adenomas compared to other PitNET is now well established. Moreover, although DAs therapy does not represent the first-line therapy for other PitNET, off-label use of DAs is considered in PitNET expressing D2DR. Nevertheless, DAs primary or secondary resistance, occurring in a subset of patients, may involve several molecular mechanisms, presently not fully elucidated. Dopamine receptors (DRs) expression is a prerequisite for a proper DA function in PitNET and several molecular events may negatively modify DR membrane expression, through the DRs down-regulation and intracellular trafficking, and DR signal transduction pathway. The current mini-review will summarise the presently known molecular events that underpin the unsuccessful therapy with DAs.

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.

Regulation of B Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B cell non-Hodgkin lymphomas (B-NHLs). In the last decade, emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma like diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer

KRAS mutations are one of the most prevalent oncogenic alterations in cancer. Until recently, drug development targeting KRAS did not convey clinical benefits to patients. Specific KRASG12C inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein’s mutant structure and block KRASG12C in its GDP-bound inactive state. Phase 1/2 trials have shown promising anti-tumor activity, especially in pretreated non-small cell lung cancer patients. As expected, both primary and secondary resistance to KRASG12C inhibitors invariably occurs, and molecular mechanisms have been characterized in pre-clinical models and patients. Several mechanisms such as tyrosine kinase receptors (RTKs) mediated feedback reactivation of ERK-dependent signaling can result in intrinsic resistance to KRAS target therapy. Acquired resistance to KRASG12C inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRASG12C inhibitors in KRASG12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.

Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors’ efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

The Emerging Role of Ferroptosis in Liver Diseases

Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.

Plasticity of extrachromosomal and intrachromosomal BRAF amplifications in mediating targeted therapy dosage challenges

Cancer cells display two modes of focal amplifications (FAs), extrachromosomal DNA/double-minutes (ecDNA/DMs) and intrachromosomal homogenously staining regions (HSRs). Understanding the plasticity of these two modes is critical for preventing targeted therapy resistance. We developed a combined BRAF plus MEK inhibitor resistance melanoma model that bears high BRAF amplifications through both DM and HSR modes, and investigated FA dynamics in the context of drug resistance plasticity. Cells harboring FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of pre-existing subpopulations. We found that copy number plasticity is not exclusive to DMs. Single cell-derived clones with HSRs also exhibit BRAF copy number and corresponding HSR length plasticity that allows them to respond to dose reduction and recover from drug addiction. Upon kinase inhibitor escalation, we observed reproducible selection for cells with BRAF kinase domain duplications residing on DMs. In sum, the plasticity of FAs allows cancer cells to respond to drug dose changes through a myriad of mechanisms. These mechanisms include increases or decreases in DMs, shortening of HSRs, acquisition of secondary resistance mechanisms, and expression of alternative slicing oncogene variants. These results highlight the challenges in targeting the cellular vulnerabilities tied to focal amplifications.

The Potential CircRNAs in Imatinib Resistance of GIST

Background: Recent studies have found that circular RNA is an abundant RNA species, belongs to part of the competing endogenous RNA network(ceRNA), which was proved to play an important role in the development, diagnosis and progress of diseases.Methods: We determined the expression of circular RNAs in paired normal gastric tissues(N), primary GIST (gastrointestinal stromal tumor) tissues (Y or YC) and imatinib mesylate secondary resistance GIST tissues(C) with microarray and predicted 8677 dysregulated circular RNAs.Results: We identified 15 circRNAs was up-regulated and 8 circRNAs were down-regulated in C group. Gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these host linear transcripts that differentially express circular RNAs are involved in many key biological pathways., predicting the potential tumor-genesis and drug resistance mechanism was related with HIF-1 pathway, later we draw the cirRNA-miRNA-mRNA network involved in the HIF-1 pathway, found that several dysregulated circRNAs and the relationship between circRNA-miRNAs-mRNA, such as circRNA_06551, circRNA_14668, circRNA_04497, circRNA_08683, circRNA_09923(Green, down-regulation) and circRNA_23636, circRNA_15734(Red, up-regulation). Conclusions: Taken together, we identified a panel of dysregulated circRNAs that may be potential biomarkers even therapy relevant to the GIST, especially imatinib secondary resistance GIST.

From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma

Immunotherapy has revolutionized the treatment landscape for many cancer types. The treatment for renal cell carcinoma (RCC) has especially evolved in recent years, from cytokine-based immunotherapies to immune checkpoint inhibitors. Although clinical benefit from immunotherapy is limited to a subset of patients, many combination-based approaches have led to improved outcomes. The success of such approaches is a direct result of the tumor immunology knowledge accrued regarding the RCC microenvironment, which, while highly immunogenic, demonstrates many unique characteristics. Ongoing translational work has elucidated some of the mechanisms of response, as well as primary and secondary resistance, to immunotherapy. Here, we provide a comprehensive review of the RCC immunophenotype with a specific focus on how preclinical and clinical data are shaping the future of immunotherapy.