Therapy Resistance Research Articles

KRAS inhibitors in drug resistance and potential for combination therapy.

Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRASG12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRASG12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.

Deciphering the topological landscape of glioma using a network theory framework

Glioma stem cells have been recognized as key players in glioma recurrence and therapeutic resistance, presenting a promising target for novel treatments. However, the limited understanding of the role glioma stem cells play in the glioma hierarchy has drawn controversy and hindered research translation into therapies. Despite significant advances in our understanding of gene regulatory networks, the dynamics of these networks and their implications for glioma remain elusive. This study employs a systemic theoretical perspective to integrate experimental knowledge into a core endogenous network model for glioma, thereby elucidating its energy landscape through network dynamics computation. The model identifies two stable states corresponding to astrocytic-like and oligodendrocytic-like tumor cells, connected by a transition state with the feature of high stemness, which serves as one of the energy barriers between astrocytic-like and oligodendrocytic-like states, indicating the instability of glioma stem cells in vivo. We also obtained various stable states further supporting glioma’s multicellular origins and uncovered a group of transition states that could potentially induce tumor heterogeneity and therapeutic resistance. This research proposes that the transition states linking both glioma stable states are central to glioma heterogeneity and therapy resistance. Our approach may contribute to the advancement of glioma therapy by offering a novel perspective on the complex landscape of glioma biology.

Axl and EGFR Dual-Specific Binding Affibody for Targeted Therapy in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a tumor of the head and neck, with a higher incidence in southern China and Southeast Asia. Radiotherapy and chemotherapy are the main treatments; however, metastasis and recurrence remain the main causes of treatment failure. Further, the majority of patients are diagnosed in the late stage due to lack of tumor-specific biomarker for early diagnosis. Therefore, an effective treatment and early detection can improve the outcome of patient with NPC. Axl and EGFR are co-expressed in NPC tissues and play key roles in tumor proliferation, migration, and invasion, which are often correlated with poor prognosis and therapy resistance. In this study, we generated a novel bispecific affibody (Z239-1907) for the dual targeting and inhibition of Axl and EGFR expression in NPC-positive cells both in vitro and in vivo. The in vitro experiments demonstrated that Z239-1907 had more pronounced antitumor effects than either modality alone (ZAXL239 or ZEGFR1907) in NPC-positive cells. Further, mice bearing NPC-positive tumors showed significant inhibition in tumor growth after treatment with Z239-1907 compared to ZAXL239 and ZEGFR1907. The in vivo tumor targeting ability and imaging also showed that Z239-1907 specifically and selectively targeted NPC xenograft mice models and accumulate at tumor site as early as 30 min and disappeared within 24 h post-injection. Collectively, these results suggest that Z239-1907 dual-target affibody is a promising therapeutic agent and a molecular imaging probe for early diagnosis in NPC.

Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy.

Nerve-cancer crosstalk has gained substantial attention owing to its impact on tumour growth, metastasis and therapy resistance. Effective therapeutic strategies targeting tumour-associated nerves within the intricate tumour microenvironment remain a major challenge in pancreatic cancer. Here we develop Escherichia coli Nissle 1917-derived outer membrane vesicles conjugated with nerve-binding peptide NP41, loaded with the tropomyosin receptor kinase (Trk) inhibitor larotrectinib (Lar@NP-OMVs) for tumour-associated nerve targeting. Lar@NP-OMVs achieve efficient nerve intervention to diminish neurite growth by disrupting the neurotrophin/Trk signalling pathway. Moreover, OMV-mediated repolarization of M2-like tumour-associated macrophages to an M1-like phenotype results in nerve injury, further accentuating Lar@NP-OMV-induced nerve intervention to inhibit nerve-triggered proliferation and migration of pancreatic cancer cells and angiogenesis. Leveraging this strategy, Lar@NP-OMVs significantly reduce nerve infiltration and neurite growth promoted by gemcitabine within the tumour microenvironment, leading to augmented chemotherapy efficacy in pancreatic cancer. This study sheds light on a potential avenue for nerve-targeted therapeutic intervention for enhancing pancreatic cancer therapy.

Mitochondrial Proteome Defined Molecular Pathological Characteristics of Oncocytic Thyroid Tumors.

Oncocytic thyroid tumors are characterized by an elevated mitochondrial density within the cells, distinguishing them from other thyroid tumors, exhibit distinct clinical behaviors, including increased invasiveness and iodine therapy resistance. However, the proteomic alterations in oncocytic thyroid tumors remain inadequately characterized. In this study, we analyzed 156 Asian patients with oncocytic thyroid adenomas (OA) and carcinomas (OCA) to explore their clinical, genetic, and proteomic features. Genetic testing of 73 samples revealed frequent mutations in TERT, NRAS, EIF1AX, EZH1, and HRAS, with TERT promoter mutations being exclusive to OCAs. Proteomic analysis identified 66 mitochondrial-specific proteins significantly highly expressed in oncocytic tumors than in non-oncocytic tumors. This led to the development of a thyroid oncocytic score (TOS) to quantify oncocytic characteristics. Among these proteins, isocitrate dehydrogenase 2 (IDH2) was substantially overexpressed in oncocytic tumors and further confirmed by immunohistochemistry in oncocytic tumor slides (n = 41) and non-oncocytic tumor slides (n = 40). Moreover, IDH2 is significantly overexpressed in OCA compared to OA highlighting its potential as a biomarker for differential diagnosis of oncocytic tumors and malignancy. These findings improve the understanding of oncocytic thyroid tumors molecular pathology and suggest IDH2 as a valuable marker for clinical management.

A Comprehensive Review of Breast Cancer: Prevalence, Diagnosis, and Gender Disparities

Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide, with significant variations in prevalence, diagnosis, and outcomes across different regions and genders. This comprehensive review examines the global and regional epidemiology of breast cancer, highlighting the increasing incidence driven by demographic changes, lifestyle factors, and urbanization. It explores the impact of gender on breast cancer, noting unique challenges faced by men and women, including diagnostic delays and treatment disparities. The review delves into the risk factors associated with breast cancer, such as genetic mutations, hormonal influences, and lifestyle choices, and discusses advancements in diagnostic technologies, including mammography, ultrasound, MRI, and emerging tools like liquid biopsies and AI-based imaging. Treatment options are analyzed, focusing on personalized medicine, targeted therapies, and the challenges of therapy resistance and recurrence. Preventive strategies, including lifestyle modifications, prophylactic surgeries, and chemoprevention, are reviewed alongside public health initiatives aimed at increasing awareness and screening. The psychosocial impact of breast cancer on patients and their families is also addressed, emphasizing the need for supportive care, patient advocacy, and integrative approaches to improve quality of life. The review concludes with recommendations for future research, policy initiatives, and strategies to address gender disparities and enhance breast cancer care globally. Keywords: Breast Cancer, Epidemiology, Gender Disparities, Risk Factors, Diagnosis

State primary standard for units of absorbed dose and absorbed dose rate of photon, electron, proton radiation and in carbon ion beams, quantity, fuence, fux density and energy of particles in proton beams and heavy charged particles GET 38-2024

The problem of ensuring the accuracy and traceability of the measurement results of the absorbed dose in carbon ion beams, as well as the measurement results of the amount, fluence, flux density and energy of particles in proton and heavy charged particles beams is considered. Until now, in practice, these values have been measured only by indirect methods. The lack of approved measuring instruments for the quantities under consideration and the metrological traceability of measurement results of these quantities to standards did not allow achieving consistency of measurement methods used in practice and confirming the reliability of the results obtained. To solve this problem, three measuring complexes have been developed and created, which are included in the State Primary Standard of units of absorbed dose and absorbed dose rate of photon, electron, proton radiation and in carbon ion beams, quantity, fluence, flux density and energy of particles in proton and heavy charged particles beams GET 38-2024. The measuring complex for reproducing the unit of absorbed dose in carbon ion beams consists of an adiabatic calorimeter, a thermostating system, a data collection and processing system and a vacuum pumping station. To reproduce the unit of energy of protons and heavy charged particles, a complex has been implemented, which includes a total absorption calorimeter, a data collection and processing system, a vacuum pumping station and a particle count determination system based on the use of a Faraday cup. To reproduce the units of fluence and particle flux density in proton and heavy charged particles beams, a measuring complex has been created containing a Faraday cup, a set of collimators and a low current meter. The schemes, the principles and the results of studies of the metrological characteristics of the developed measuring complexes are described. The results are relevant for the field of radiation therapy and radiation resistance tests of the electronic component base used in the space industry.

Functional Roles of Long Non-coding RNAs on Stem Cell-related Pathways in Glioblastoma

: Long non-coding RNAs (lncRNAs), characterized by their length exceeding 200 nucleotides and lack of protein-coding capacity, are intricately associated with a wide array of cellular processes, encompassing cell invasion, differentiation, proliferation, migration, apoptosis, and regeneration. Perturbations in lncRNA expression have been observed in numerous diseases and have emerged as pivotal players in the pathogenesis of diverse tumor types. Glioblastoma, a highly malignant primary tumor of the central nervous system (CNS), remains a formidable challenge even with the advent of novel therapeutic interventions, as primary glioblastomas invariably exhibit therapy resistance and aggressive behavior. Glioblastomas can arise from progenitor cells or neuroglial stem cells, revealing profound cellular heterogeneity, notably in the form of glioblastoma stem cells (GSCs) possessing stem-like properties. Glioblastomas comprise neural precursors that harbor essential characteristics of neural stem cells (NSCs). Several signaling pathways have been implicated in the regulation of self-renewal in both cancer cells and stem cells. In addition to their involvement in therapy resistance and survival of glioblastoma, lncRNAs are implicated in the modulation of GSC behaviors through diverse pathways and the intricate regulation of various genes and proteins. This review aims to comprehensively discuss the interplay between lncRNAs, their associated pathways, and GSCs, shedding light on their potential implications in glioblastoma.

Integrated single-cell transcriptomic analyses identify a novel lineage plasticity-related cancer cell type involved in prostate cancer progression

Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging. Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples=3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples=93, cells=222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, invitro and invivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings. We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype. Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa. This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).

Cancer Stem Cells and Treatment of Cancer: An Update and Future Perspectives.

Cancer stem cells (CSCs) play an essential role in tumour progression and metastasis. Stem cell ability of self-renewal enables it to persist over time, thereby contributing to cancer relapse or recurrence and also resistance to current therapies. Therefore, targeting CSCs emerged as a promising strategy of cancer treatment. CSCs exhibit differentiation, self-renewal, and plasticity, they contribute to formation of malignant tumours, also favors, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Coventional cancer treatments predominantly target cancer cells that are not CSCs, CSCs frequently survive, eventually leading to relapse. This article focuses on the development of novel therapeutic strategies that combine conventional treatments and CSC inhibitors to eradicate cancer cells and CSCs, for the better and permanent treatment. However, the diversity of CSCs is a significant obstacle in the development of CSC-targeted therapies, necessitating extensive research for a better understanding and exploration of therapeutic approaches. Future development of CSC-targeted therapies will rely heavily on overcoming this obstacle.

Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2

Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC50 value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.

The potential of targeted radionuclide therapy to treat hypoxic tumor cells

Tumor hypoxia contributes to cancer progression and therapy resistance. Several strategies have been investigated to relieve tumor hypoxia, of which some were successful. However, their clinical application remains challenging and therefore they are not used in daily clinical practice. Here, we review the potential of targeted radionuclide therapy (TRT) to eradicate hypoxic cancer cells. We present an overview of the published TRT strategies using β−-particles, α-particles, and Auger electrons. Altogether, we conclude that α-particle emitting radionuclides are most promising since they can cause DNA double strand breaks independent of oxygen levels. Future directions for research are addressed, including more adequate in vitro and in vivo models to proof the potential of TRT to eliminate hypoxic cancer cells. Furthermore, dosimetry and radiobiology are identified as key to better understand the mechanism of action and dose-response relationships in hypoxic tumor areas. Finally, we can conclude that in order to achieve long-term anti-tumor efficacy, TRT combination treatment strategies may be necessary.

Regulation of autophagy by Rab27B in colorectal cancer

Autophagy is a cellular recycling process that is associated with tumor growth, anti-tumor immune responses, and therapy resistance in colorectal cancer (CRC). In this report, we identify the small GTPase Rab27B to control the autophagy process in CRC. Depletion of Rab27B showed an abnormal accumulation of autophagy vesicles and increased autophagy markers in CRC cells, indicating autophagy dysregulation. Image analysis indicated that autophagy flux is blocked at the autophagosome/lysosome fusion step when Rab27B is lost. While Rab27B deficient cells are proficient at growth under 2D in vitro conditions, cell growth was significantly impacted in both in vitro 3D growth and in vivo tumorigenesis studies. Together, these results demonstrate a new role of Rab27B in the autophagy trafficking process in CRC and identify Rab27B as a potential therapeutic target for CRC.

Central role of hypoxia-inducible factor-1α in metabolic reprogramming of cancer cells: A review.

Metabolic reprogramming is one of the characteristics of tumor cell metabolism. In tumor cells, there are multiple metabolic enzymes and membrane proteins to regulate metabolic reprogramming, and hypoxia inducible factor-1α (HIF-1α) can be regulated in transcription, translation, posttranslational modification and other aspects through multiple pathways, and HIF-1α affects multiple metabolic enzymes and membrane proteins during metabolic reprogramming, thus playing a central role in the metabolic reprogramming process, and thus has some implications for tumor therapy and understanding chemotherapy drug resistance. HIF-1α affects a number of metabolic enzymes and membrane proteins in the metabolic reprogramming process, thus playing a central role in the metabolic reprogramming process, which has certain significance for the treatment of tumors and the understanding of chemotherapeutic drug resistance. In this paper, we review the central role of HIF-1α in metabolic reprogramming, chemotherapeutic agents targeting HIF-1α, and chemotherapeutic drug resistance.

The role of ABCG2 in health and disease: Linking cancer therapy resistance and other disorders

The role of ABCG2 in health and disease: Linking cancer therapy resistance and other disorders

VCAN in the extracellular matrix drives glioma recurrence by enhancing cell proliferation and migration

IntroductionGliomas are the most prevalent primary malignant intracranial tumors, characterized by high rates of therapy resistance, recurrence, and mortality. A major factor contributing to the poor prognosis of gliomas is their ability to diffusely infiltrate surrounding and even distant brain tissues, rendering complete total resection almost impossible and leading to frequent recurrences. The extracellular matrix (ECM) plays a key role in the tumor microenvironment and may significantly influence glioma progression, recurrence, and therapeutic response.MethodsIn this study, we first identified the ECM and the Versican (VCAN), a key ECM protein, as critical contributors to glioma recurrence through a comprehensive analysis of transcriptomic data comparing recurrent and primary gliomas. Using single-cell sequencing, we revealed heterogeneous distribution patterns and extensive intercellular communication among ECM components. External sequencing and immunohistochemical (IHC) staining further validated that VCAN is significantly upregulated in recurrent gliomas and is associated with poor patient outcomes.ResultsFunctional assays conducted in glioma cell lines overexpressing VCAN demonstrated that VCAN promotes cell proliferation and migration via the PI3K/Akt/AP-1 signaling pathway. Furthermore, inhibiting the PI3K/Akt pathway effectively blocked VCAN-mediated glioma progression.ConclusionThese findings provide valuable insights into the mechanisms underlying glioma recurrence and suggest that targeting both VCAN and the PI3K/Akt pathway could represent a promising therapeutic strategy for managing recurrent gliomas.

Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes.

Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM. Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence. In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes. MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses. Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels. Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes. Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes. Elevated collagen levels were associated with reduced tumour-infiltrating lymphocytes.

Exploring the Role of Cuprotosis-Associated Genes in Cancer Progression and Therapy Resistance: A Comprehensive Analysis across Multiple Cancer Types

This review presents a comprehensive overview of the role of cuprotosis-associated genes in various cancer types, highlighting their significance in tumor progression and therapy resistance. In breast cancer and colorectal cancer (CRC), dysregulation of genes involved in mitochondrial function and copper metabolism, such as FDX1, LIAS, LIPT1, DLD, DLAT, and PDHA1/PDHB, promotes metabolic reprogramming and enhances cancer cell survival. Ovarian cancer exhibits unique dysregulations in genes like ATP7B, CCS, and COMMD1, influencing copper metabolism and redox signaling pathways, thereby contributing to chemoresistance and tumor growth. Head and neck cancer involves upregulation of MT1X, ATP7A, and CCS, potentially aiding cancer cell survival under oxidative stress conditions. Lung cancer is characterized by distinct dysregulation of genes like SLC31A1, ATOX1, and COMMD1, modulating copper homeostasis and redox signaling to support tumor proliferation. Liver cancer and kidney cancer each present unique sets of dysregulated cuprotosis-associated genes, such as SLC39A4, SCO2, and ATP7A, suggesting novel therapeutic targets specific to these cancer types. Pathway analysis reveals enrichment in mineral absorption pathways, emphasizing the importance of these genes in maintaining cellular mineral homeostasis. Understanding the intricate interplay between cuprotosis-associated genes and cancer biology offers insights into potential therapeutic strategies targeting copper metabolism for improved treatment outcomes across various cancer types.

Influence of Nanomedicine as a Smart Weapon on Multidrug Resistance in Cancer Therapy.

Cancer is the leading cause of death worldwide. The effectiveness of chemotherapy in cancer patients is still significantly hampered by Multidrug Resistance (MDR). Tumors exploit the MDR pathways to invade the host and limit the efficacy of chemotherapeutic drugs that are delivered as single drugs or combinations. Further, overexpression of ATP-binding Cassette transporter (ABC transporter) proteins augments the efflux of chemotherapeutic drugs and lowers their intracellular accumulation. Recent progress in the development of nanotechnology and nanocarrier-based drug delivery systems has shown a better perspective with respect to the improvement of cancer chemotherapy. Nanoparticles/nanomaterials are designed to target the immune system and tumor microenvironment of cancer cells for a variety of cancer treatments in order to improve bioavailability and reduce toxicity. This review elucidates the successful use of nanomaterials for cancer therapy and addressing the MDR and throws some light on the present obstacles impeding their translation to clinical use.

Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma.

Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years. Recent therapies, notably immunotherapy and targeted therapy, have significantly improved the outcome of patients with metastatic melanoma. Previously dismal five-year survival rates of below 5% have shifted to over 50% of patients surviving the five-year mark, marking a significant shift in the landscape of melanoma treatment and survival. Unfortunately, about 50% of patients either do not respond to therapy or experience early or late relapses following an initial response. The underlying mechanisms for primary and secondary resistance to targeted therapies or immunotherapy and relapse patterns remain not fully identified. However, several molecular pathways and genetic factors have been associated with melanoma resistance to these treatments. Understanding these mechanisms paves the way for creating novel treatments that can address resistance and ultimately enhance patient outcomes in melanoma. This review explores the mechanisms behind immunotherapy and targeted therapy resistance in melanoma patients. Additionally, it describes the treatment strategies to overcome resistance, which have improved patients' outcomes in clinical trials and practice.