• Issue
    Volume 18, Issue 2
    239-471
    February 2024

Issue Information

Open Access

Issue Information

  • Pages: 239-240
  • First Published: 07 February 2024
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The issue features content focused on fighting cancer by various therapeutic approaches and overcoming drug resistance. Read the Viewpoint on drug resistance by Mariangela Russo in pp. 241–244 and the meeting report on strategies to decrease inequalities in cancer therapeutics, care and prevention by Ulrik Ringborg et al. in pp. 245–279.

On the cover: mPGES-1 inhibition enhances the efficacy of vinblastine in neuroblastoma spheroids, illustrated with live/dead probes. Read the full article by Ahlem Zaghmi et al. in pp. 317–335.

Viewpoint

Open Access

Genetic and non-genetic drug resistance: Darwin or Lamarck?

  • Pages: 241-244
  • First Published: 02 February 2024
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Genetic and non-genetic mechanisms of drug resistance may co-occur and co-operate in cancer cell populations providing fitter cellular states able to resist to the lethal effect of anti-cancer therapies. Notably, both Darwinian selection and Lamarckian drug-induced adaptation may be involved in the development of drug resistance. A broader characterization of these phenomena is warranted to guarantee more effective therapeutic approaches.

Meeting Report

Open Access

Strategies to decrease inequalities in cancer therapeutics, care and prevention: Proceedings on a conference organized by the Pontifical Academy of Sciences and the European Academy of Cancer Sciences, Vatican City, February 23–24, 2023

  • Pages: 245-279
  • First Published: 22 December 2023
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Here we summarize the conference proceedings of the second meeting on Cancer organized by the Pontifical Academy of Sciences together with the European Academy of Cancer Sciences. Despite the growing advances in cancer research, cancer incidence and prevalence are on the rise especially in countries with poor economic standing, which leads to a global inequality problem. The increasing demands for infrastructure support in innovative research and implementation of research outcomes in healthcare and prevention programs were discussed at the meeting. Establishing infrastructures in translational research that are sustainable and accessible for all patients is crucial in addressing inequalities in cancer treatment.

Short Report

Open Access

Enhanced reversal of ABCG2-mediated drug resistance by replacing a phenyl ring in baicalein with a meta-carborane

  • Pages: 280-290
  • First Published: 20 September 2023
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Multidrug resistance mediated by the breast cancer resistance protein (BCRP, ABCG2) is challenging in cancer therapy. Therefore, combined use of ABCG2 inhibitors with anticancer agents seems to be useful to overcome drug resistance. Based on baicalein, used in traditional Chinese medicine, we replaced a phenyl group by boran-based cluster (meta-carborane) to enhance ABCG2 inhibition and successfully reversed mitoxantrone resistance.

Research Articles

Open Access

Urinary comprehensive genomic profiling predicts urothelial carcinoma recurrence and identifies responders to intravesical therapy

  • Pages: 291-304
  • First Published: 27 September 2023
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This study used genomic profiling to detect mutations associated with urothelial carcinoma in patient urine samples collected before and after intravesical therapy. Genomic profiles informed an algorithmic assessment of minimal residual disease, which accurately predicted recurrence risk after surgery and quantified molecular response to therapy. These findings demonstrate the utility of genomics to inform personalized risk stratification.

Open Access

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study

  • Pages: 305-316
  • First Published: 21 October 2023
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This study explored biomarkers of adjuvant therapy for resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer using tumor specimens from the phase III IMPACT study. NOTCH1 co-mutation can serve as a poor prognostic factor for overall survival in the gefitinib group while probably predicting a poor response to adjuvant EGFR-TKI. Meanwhile, CREBBP co-mutation may be a biomarker for predicting a poor response to adjuvant platinum-based chemotherapy.

Open Access

High-content screening of drug combinations of an mPGES-1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance

  • Pages: 317-335
  • First Published: 30 July 2023
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This study highlights the value of spheroids for screening drug combinations and selecting appropriate hits for preclinical testing. A low-cost spheroid model was developed that combines viability testing and confocal imaging to increase the reliability of results. Further research is needed to fully investigate the mechanisms underlying the synergies between microsomal prostaglandin E synthase-1 inhibitors and chemotherapeutic agents.

Open Access

A novel pipeline for prioritizing cancer type-specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas

  • Pages: 336-349
  • First Published: 23 November 2023
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This study provides a template for using the public CRISPR screen data in DepMap to identify novel therapeutic targets for specific cancer types and rapidly advance them toward clinical application. As an example, we used the gene dependency data in DepMap for HPV-negative head and neck cancer to demonstrate application of the pipeline, which integrates the CRISPR data with multiple other publicly available resources to identify the most promising targets.

Open Access

Targeting tumor O-glycosylation modulates cancer–immune-cell crosstalk and enhances anti-PD-1 immunotherapy in head and neck cancer

  • Pages: 350-368
  • First Published: 15 July 2023
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This study found that O-glycan truncation induced proteasomal degradation of interleukin-6 to suppress tumor growth by promoting M1 macrophage polarization and enhancing T cell-mediated cytotoxicity in head and neck cancer in vitro and in vivo. Combining an O-glycosylation inhibitor with anti-programmed cell death protein 1 antibody effectively suppressed tumor growth, emphasizing the role of O-glycosylation in modulating the tumor microenvironment.

Open Access

Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

  • Pages: 369-385
  • First Published: 22 October 2023
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Using the combination of whole genome CRISPR-Cas9 screening, RNA interference screens, proteomic mass spectrometry profiling and small molecule inhibitors, Baxter et al. demonstrate that loss of FBXW7 in tumour cells imparts a synthetic lethal effect with CDC7 inhibition.

Open Access

Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance

  • Pages: 386-414
  • First Published: 16 October 2023
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Microtubule-targeting agents combat cancer, but resistance and adverse effects hinder their use. Employing gene expression-based repositioning, we identified VU-0365114 as a microtubule-destabilizing agent. It shows broad-spectrum anticancer activity, particularly in colorectal cancer cells. VU-0365114 overcomes multidrug resistance (MDR) and lacks significant off-target effects. Repurposing VU-0365114 holds promise for cancer treatment and resistance reversal.

Open Access

A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance

  • Pages: 415-430
  • First Published: 17 December 2023
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Ba/F3 cells expressing JAK2-V617F treated with 4 μm of ruxolitinib displayed a 45-kDa JAK2 variant by in-frame fusion consisting of the N-terminal 77 amino acids (a.a.) together with residues 814–1132 a.a of the kinase domain (FERM-JAK2). FERM-JAK2 is constitutively dimerized and activates STAT5 without receptor interaction. FERM-JAK2 is resistant toward JAK2-ATP competitive inhibitors and induces the lethal MPN-like phenotype in mice.

Open Access

Subcellular localization of PD-L1 and cell-cycle-dependent expression of nuclear PD-L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy

  • Pages: 431-452
  • First Published: 16 December 2023
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Both the membrane and nucleus of head and neck cancer cells express PD-L1. PD-L1 is translocated from the membrane into the nucleus via vimentin. We detected high-molecular-weight PD-L1 variants in the nucleus. Their expression is cell-cycle-dependent and involves interaction with proteins related to DNA remodeling and mRNA splicing. Multimerization likely causes PD-L1's high weight in cancer patient tumors.

Open Access

Transcriptional analysis of landmark molecular pathways in lung adenocarcinoma results in a clinically relevant classification with potential therapeutic implications

  • Pages: 453-470
  • First Published: 09 November 2023
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We classified lung adenocarcinoma (LUAD) tumors into seven subtypes, based on the transcriptional activity of 50 pathways. Subtypes were associated with distinct molecular and clinical features. Despite significant challenges, we believe that integration of transcriptomic and genomic data may pave the way for guiding novel therapeutic approaches in patients with LUAD.