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The transforming growth factor β (TGF-β) pathway, which is well studied for its ability to inhibit cell proliferation in early stages of tumorigenesis while promoting epithelial-mesenchymal transition and invasion in advanced cancer, is considered to act as a double-edged sword in cancer. Multiple inhibitors have been developed to target TGF-β signaling, but results from clinical trials were inconsistent, suggesting that the functions of TGF-β in human cancers are not yet fully explored. Multiple drug resistance is a major challenge in cancer therapy; emerging evidence indicates that TGF-β signaling may be a key factor in cancer resistance to chemotherapy, targeted therapy and immunotherapy. Finally, combining anti-TGF-β therapy with other cancer therapy is an attractive venue to be explored for the treatment of therapy-resistant cancer.

Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.

Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.

Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA–dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM. Cancer cells reprogram their metabolism in response to growth factor receptor mutations. However, the effect of altered nutrient levels on oncogenic signaling and therapeutic response is not well understood. We demonstrate that glucose or acetate, two abundant “fuel” sources in the brain, promote epidermal growth factor receptor vIII (EGFRvIII)-dependent signaling through activation of mechanistic target of rapamycin complex 2 (mTORC2) by acetylation of its core component Rictor. This activity is mediated through elevated levels of acetyl-CoA. A surprising implication of this study is that glucose or acetate can contribute to targeted therapy resistance by maintaining signaling through downstream components of the growth factor receptor signaling cascade.

Therapeutic resistance is a formidable barrier in cancer treatment, necessitating innovative solutions to enhance drug efficacy. Exosomes, with their unparalleled biocompatibility, low immunogenicity, and robust cargo protection, have emerged as groundbreaking nanocarriers. This review unveils the transformative potential of exosomes in overcoming drug resistance - encompassing chemotherapy, targeted therapy, and immunotherapy - in a wide spectrum of tumors. Through advanced genetic and non-genetic modifications, exosomes can dramatically enhance drug targeting and cytotoxicity, offering unprecedented precision in treatment. We explore state-of-the-art exosome engineering techniques, their revolutionary applications in clinical trials, and their promise as the next Frontier in therapeutic innovation. This comprehensive review aims to capture the cutting-edge developments and future directions of exosome-based therapies, positioning them as a cornerstone of next-generation oncology.

Objectives To compare drug-eluting transarterial chemoembolization (DE-TACE) followed by systemic chemotherapy versus systemic chemotherapy alone for advanced lung adenocarcinoma that has progressed after targeted therapy. Materials and methods All patients undergoing DE-TACE followed by systemic chemotherapy (DE-TACE group) or systemic chemotherapy alone (chemotherapy group) for stage III-IV lung adenocarcinoma from January 2018 to January 2022 were screened. On day 1 of each 21-day cycle, patients received pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ). Patients in the DE-TACE group received cisplatin (75 mg/m 2 ) and gemcitabine (600 mg/m 2 ) via the feeding arteries and then embolization using drug-eluting beads carrying gemcitabine (400 mg). DE-TACE was repeated if deemed necessary based on CT examination three weeks later. Overall survival (OS) and treatment-emergent adverse events (TEAEs) were compared in the overall cohort, as well as propensity score-matched (PSM) cohort (1:1 ratio with 0.05 caliper width). Results The final analysis included 62 and 69 patients in the chemotherapy and DE-TACE groups, respectively. Within the 49-month median follow-up, the median OS was 18.3 months and 33.6 months in the chemotherapy and DE-TACE groups, respectively, with a hazard ratio (HR) of 0.18 (95% CI 0.1–0.32; P  < 0.001). In the PSM analysis (36 patients per group), the median OS was 18.3 and 33.1 months in the chemotherapy and DE-TACE groups, respectively (HR 0.11, 95% CI 0.05–0.26; P  < 0.001). The rate of grade 3 or higher TEAEs in the PSM analysis was 44.4% (16/36) in the chemotherapy group versus 5.6% (2/36) in the DE-TACE group ( P  < 0.001). Conclusion Compared to chemotherapy alone, DE-TACE followed by chemotherapy was associated was associated with significantly prolonged overall survival and substantially reduced high-grade treatment-related toxicity in patients with lung adenocarcinoma that progressed after targeted therapy.

Acquired resistance represents a critical clinical challenge to molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) treatment in hepatocellular carcinoma (HCC). Therefore, it is urgent to explore new mechanisms and therapeutics that can overcome or delay resistance. Here, a US Food and Drug Administration (FDA)‐approved pleuromutilin antibiotic is identified that overcomes sorafenib resistance in HCC cell lines, cell line‐derived xenograft (CDX) and hydrodynamic injection mouse models. It is demonstrated that lefamulin targets interleukin enhancer‐binding factor 3 (ILF3) to increase the sorafenib susceptibility of HCC via impairing mitochondrial function. Mechanistically, lefamulin directly binds to the Alanine‐99 site of ILF3 protein and interferes with acetyltransferase general control non‐depressible 5 (GCN5) and CREB binding protein (CBP) mediated acetylation of Lysine‐100 site, which disrupts the ILF3‐mediated transcription of mitochondrial ribosomal protein L12 (MRPL12) and subsequent mitochondrial biogenesis. Clinical data further confirm that high ILF3 or MRPL12 expression is associated with poor survival and targeted therapy efficacy in HCC. Conclusively, this findings suggest that ILF3 is a potential therapeutic target for overcoming resistance to TKIs, and lefamulin may be a novel combination therapy strategy for HCC treatment with sorafenib and regorafenib. Lefamulin overcomes drug resistance of hepatocellular carcinoma (HCC) by targeting interleukin enhancer‐binding factor 3 (ILF3) and interfering with general control non‐depressible 5 (GCN5) and CREB binding protein (CBP)‐mediated acetylation, which inhibits mitochondrial ribosomal protein L12 (MRPL12) transcription and regulates mitochondrial homeostasis. Lefamulin may be a novel combination therapy strategy for HCC treatment with tyrosine kinase inhibitors (TKIs).

Background/objective: Mucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with few cases having targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are necessary to address therapeutic resistance. The relatively greater incidence of naturally occurring MM in dogs, as well as its comparable clinical and pathological characteristics to human MM, represents an opportunity for study as a human MM patient surrogate. Resistance-promoting crosstalk between Ras/MAPK and PI3K/AKT/mTOR signaling under trametinib inhibition of MEK was studied in canine MM. Emphasis was placed on the suppressive effect of trametinib on cell cycle entry and its potential role in drug resistance. Methods: D-type cyclins were investigated following trametinib treatment of five MM cell lines exhibiting differential drug sensitivities. Signaling pathway activation, proliferation, survival, cell death, and cell cycle were analyzed in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knockdown or inducible recombinant overexpression. Results: Trametinib diminished cyclin D1 in all cell lines. While relatively trametinib-resistant MM cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, sensitive MM cells lacked similar cyclin D2 compensation. Inhibition of the compensatory cyclin D2 in resistant cells conferred sensitivity. Induced cyclin D2 overexpression in otherwise trametinib-sensitive MM cells promoted survival. Upregulated PI3K/AKT/mTOR signaling under trametinib treatment was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response. Conclusions: The compensatory switch from preferential reliance on cyclin D1 to D2 plays a role in MM resistance to MEK inhibition.

Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non‐genetic mechanisms that drive these processes. Here, we performed in vivo gain‐of‐function CRISPR screens and identified SMAD3, BIRC3, and SLC9A5 as key actors of BRAFi resistance. We show that their expression levels increase during acquisition of BRAFi resistance and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3‐signature) promotes a mesenchymal‐like phenotype and BRAFi resistance by acting as an upstream transcriptional regulator of potent BRAFi‐resistance genes such as EGFR and AXL. This SMAD3‐signature predicts resistance to both current melanoma therapies in different cohorts. Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival. Interestingly, decrease of SMAD3 activity can also be reached by inhibiting the Aryl hydrocarbon Receptor (AhR), another druggable transcription factor governing SMAD3 expression level. Our work highlights novel drug vulnerabilities that can be exploited to develop long‐lasting antimelanoma therapies. Synopsis Using a CRISPR activation screening, we identified genes involved in BRAF inhibitor (BRAFi) resistance in cutaneous melanoma. Their upregulation promoted tumour growth of therapy‐naïve melanoma cells and BRAFi‐resistance. Inhibition of these genes (not mutated) may be useful for therapy. Gene up‐regulation obtained by CRISPR activation identified new targets for cutaneous melanoma. AhR‐SMAD3 axis promoted BRAFi‐resistance and cell plasticity. The SMAD3‐signature was found in most BRAFi‐resistant human melanoma tumours. Inhibition of SMAD3 alone or in combination with BRAFi impaired survival of BRAFi‐resistant cells. Graphical Abstract Using a CRISPR activation screening, we identified genes involved in BRAF inhibitor (BRAFi) resistance in cutaneous melanoma. Their upregulation promoted tumour growth of therapy‐naïve melanoma cells and BRAFi‐resistance. Inhibition of these genes (not mutated) may be useful for therapy.

Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors. Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities. Yet, no matter how a cancer is addicted to a specific target - cancer's genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions. Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.