bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022‒12‒11
twelve papers selected by
Rana Gbyli
Yale University
  1. Breast cancer prevention by short-term inhibition of TGFβ signaling.
  2. Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit.
  3. LY6D marks pre-existing resistant basosquamous tumor subpopulations.
  4. The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location.
  5. NEDDylated Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors.
  6. An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies.
  7. Acetyl-CoA keeps PC stable.
  8. A Transitional Cell Population Is Enriched in Aggressive Human Medulloblastoma.
  9. Non-classical ferroptosis inhibition by a small molecule targeting PHB2.
  10. Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair.
  11. Targeting DNA damage response pathways in cancer.
  12. Editorial: Recent advances of drug resistance research in colorectal cancer therapy.
  1. Nat Commun. 2022 Dec 07. 13(1): 7558
    Breast cancer prevention by short-term inhibition of TGFβ signaling.
    Maša Alečković, Simona Cristea, Carlos R Gil Del Alcazar, Pengze Yan, Lina Ding, Ethan D Krop, Nicholas W Harper, Ernesto Rojas Jimenez, Donghao Lu, Anushree C Gulvady, Pierre Foidart, Marco Seehawer, Benedetto Diciaccio, Katherine C Murphy, Jason Pyrdol, Jayati Anand, Kodie Garza, Kai W Wucherpfennig, Rulla M Tamimi, Franziska Michor, Kornelia Polyak.
      Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.
    DOI:  https://doi.org/10.1038/s41467-022-35043-5
  2. Front Oncol. 2022 ;12 1004669
    Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit.
    Wenjuan Ning, Thomas M Marti, Patrick Dorn, Ren-Wang Peng.
      Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRASG12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRASG12C, such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRASG12C inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRASG12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRASG12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.
    Keywords:  EMT; KRAS G12C inhibitors; TME; non-genetic adaptive resistance; symbiosis
    DOI:  https://doi.org/10.3389/fonc.2022.1004669
  3. Nat Commun. 2022 Dec 06. 13(1): 7520
    LY6D marks pre-existing resistant basosquamous tumor subpopulations.
    Daniel Haensel, Sadhana Gaddam, Nancy Y Li, Fernanda Gonzalez, Tiffany Patel, Jeffrey M Cloutier, Kavita Y Sarin, Jean Y Tang, Kerri E Rieger, Sumaira Z Aasi, Anthony E Oro.
      Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensive understanding of the cellular states and markers associated with these populations remains poorly understood. Here we identify a pre-existing resistant cellular population in naive basal cell carcinoma tumors marked by the surface marker LY6D. LY6D+ tumor cells are spatially localized and possess basal cell carcinoma and squamous cell carcinoma-like features. Using computational tools, organoids, and spatial tools, we show that LY6D+ basosquamous cells represent a persister population lying on a central node along the skin lineage-associated spectrum of epithelial states with local environmental and applied therapies determining the kinetics of accumulation. Surprisingly, LY6D+ basosquamous populations exist in many epithelial tumors, such as pancreatic adenocarcinomas, which have poor outcomes. Overall, our results identify the resistant LY6D+ basosquamous population as an important clinical target and suggest strategies for future therapeutic approaches to target them.
    DOI:  https://doi.org/10.1038/s41467-022-35020-y
  4. Nat Genet. 2022 Dec;54(12): 1881-1894
    The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location.
    Ilon Liu, Li Jiang, Erik R Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia A Hack, Daeun Jeong, McKenzie L Shaw, Bernhard Englinger, Jenna LaBelle, Hafsa M Mire, Sibylle Madlener, Lisa Mayr, Michael A Quezada, Maria Trissal, Eshini Panditharatna, Kati J Ernst, Jayne Vogelzang, Taylor A Gatesman, Matthew E Halbert, Hana Palova, Petra Pokorna, Jaroslav Sterba, Ondrej Slaby, Rene Geyeregger, Aaron Diaz, Izac J Findlay, Matthew D Dun, Adam Resnick, Mario L Suvà, David T W Jones, Sameer Agnihotri, Jessica Svedlund, Carl Koschmann, Christine Haberler, Thomas Czech, Irene Slavc, Jennifer A Cotter, Keith L Ligon, Sanda Alexandrescu, W K Alfred Yung, Isabel Arrillaga-Romany, Johannes Gojo, Michelle Monje, Mats Nilsson, Mariella G Filbin.
      Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41588-022-01236-3
  5. Sci Adv. 2022 Dec 09. 8(49): eabq0648
    NEDDylated Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors.
    Alice Meroni, Jan Grosser, Sumedha Agashe, Natasha Ramakrishnan, Jessica Jackson, Priyanka Verma, Laura Baranello, Alessandro Vindigni.
      DNA topoisomerase 1 (TOP11) inhibitors are mainstays of anticancer therapy. These drugs trap TOP1 on DNA, stabilizing the TOP1-cleavage complex (TOP1-cc). The accumulation of TOP1-ccs perturbs DNA replication fork progression, leading to DNA breaks and cell death. By analyzing the genomic occupancy and activity of TOP1, we show that cells adapt to treatment with multiple doses of TOP1 inhibitor by promoting the degradation of TOP1-ccs, allowing cells to better tolerate subsequent doses of TOP1 inhibitor. The E3-RING Cullin 3 ligase in complex with the BTBD1 and BTBD2 adaptor proteins promotes TOP1-cc ubiquitination and subsequent proteasomal degradation. NEDDylation of Cullin 3 activates this pathway, and inhibition of protein NEDDylation or depletion of Cullin 3 sensitizes cancer cells to TOP1 inhibitors. Collectively, our data uncover a previously unidentified NEDD8-Cullin 3 pathway involved in the adaptive response to TOP1 inhibitors, which can be targeted to improve the efficacy of TOP1 drugs in cancer therapy.
    DOI:  https://doi.org/10.1126/sciadv.abq0648
  6. Cell Mol Life Sci. 2022 Dec 10. 80(1): 6
    An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies.
    Eleonora Orlando, Matúš Medo, Ariel Bensimon, Aurélie Quintin, Rahel Riedo, Selina M Roth, Carsten Riether, Thomas M Marti, Daniel M Aebersold, Michaela Medová, Ruedi Aebersold, Yitzhak Zimmer.
      PURPOSE: Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells.EXPERIMENTAL: DESIGN: We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment.
    RESULTS: We identified an 'oncogene addiction phosphorylation signature' (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments.
    CONCLUSIONS: We propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene.
    Keywords:  ALK; BRAF; DNA damage response; EGFR; MET; Oncogene addiction; Patient-derived xenografts; Protein phosphorylation; Targeted phosphoproteomics; Treatment response
    DOI:  https://doi.org/10.1007/s00018-022-04634-2
  7. Nat Struct Mol Biol. 2022 Dec 08.
    Acetyl-CoA keeps PC stable.
    Joseph Willson.
      
    DOI:  https://doi.org/10.1038/s41594-022-00902-8
  8. Cancer Discov. 2022 Dec 09. OF1
    A Transitional Cell Population Is Enriched in Aggressive Human Medulloblastoma.
      A transitional progenitor population, enhanced in aggressive medulloblastoma, was identified in human fetal cerebellum.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-215
  9. Nat Commun. 2022 Dec 03. 13(1): 7473
    Non-classical ferroptosis inhibition by a small molecule targeting PHB2.
    Wei Yang, Bo Mu, Jing You, Chenyu Tian, Huachao Bin, Zhiqiang Xu, Liting Zhang, Ronggang Ma, Ming Wu, Guo Zhang, Chong Huang, Linli Li, Zhenhua Shao, Lunzhi Dai, Laurent Désaubry, Shengyong Yang.
      Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.
    DOI:  https://doi.org/10.1038/s41467-022-35294-2
  10. Sci Adv. 2022 Dec 09. 8(49): eadd8928
    Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair.
    Liu Liu, Baicheng Lin, Shasha Yin, Lauren E Ball, Joe R Delaney, David T Long, Wenjian Gan.
      BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4 functions on transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interacts with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 recruitment to acetylated histones/chromatin. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 and highlight targeting PRMT2/4 for better antitumor effect of BET inhibitors and DNA damaging agents.
    DOI:  https://doi.org/10.1126/sciadv.add8928
  11. Nat Rev Cancer. 2022 Dec 05.
    Targeting DNA damage response pathways in cancer.
    Florian J Groelly, Matthew Fawkes, Rebecca A Dagg, Andrew N Blackford, Madalena Tarsounas.
      Cells have evolved a complex network of biochemical pathways, collectively known as the DNA damage response (DDR), to prevent detrimental mutations from being passed on to their progeny. The DDR coordinates DNA repair with cell-cycle checkpoint activation and other global cellular responses. Genes encoding DDR factors are frequently mutated in cancer, causing genomic instability, an intrinsic feature of many tumours that underlies their ability to grow, metastasize and respond to treatments that inflict DNA damage (such as radiotherapy). One instance where we have greater insight into how genetic DDR abrogation impacts on therapy responses is in tumours with mutated BRCA1 or BRCA2. Due to compromised homologous recombination DNA repair, these tumours rely on alternative repair mechanisms and are susceptible to chemical inhibitors of poly(ADP-ribose) polymerase (PARP), which specifically kill homologous recombination-deficient cancer cells, and have become a paradigm for targeted cancer therapy. It is now clear that many other synthetic-lethal relationships exist between DDR genes. Crucially, some of these interactions could be exploited in the clinic to target tumours that become resistant to PARP inhibition. In this Review, we discuss state-of-the-art strategies for DDR inactivation using small-molecule inhibitors and highlight those compounds currently being evaluated in the clinic.
    DOI:  https://doi.org/10.1038/s41568-022-00535-5
  12. Front Oncol. 2022 ;12 1059223
    Editorial: Recent advances of drug resistance research in colorectal cancer therapy.
    Chenyang Ye, Yanhong Deng, Weijing Sun, Ying Yuan.
      
    Keywords:  cancer treatment; colorectal cancer; drug resistance (DR); drug resistance mechanism; prognosis analysis
    DOI:  https://doi.org/10.3389/fonc.2022.1059223
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