scholarly journals Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

2020 ◽  
Author(s):  
Manasi K. Mayekar ◽  
Deborah R. Caswell ◽  
Natalie I. Vokes ◽  
Emily K. Law ◽  
Wei Wu ◽  
...  

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-κB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

Author(s):  
Shigeki Nanjo ◽  
Wei Wu ◽  
Niki Karachaliou ◽  
Collin M. Blakely ◽  
Junji Suzuki ◽  
...  

AbstractMolecularly targeted cancer therapy has improved outcomes for cancer patients with targetable oncoproteins, such as mutant epidermal growth factor receptor (EGFR) in lung cancer. Yet, long-term patient survival remains limited because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations in the EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alteration of the mRNA splicing factor RBM10 that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of Bcl-xS-(pro-apoptotic)-to-Bcl-xL(anti-apoptotic) Bcl-x isoforms. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Co-inhibition of Bcl-xL and mutant EGFR overcame resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations, and on the impact of splicing factor deficiency in the modulation of sensitivity to targeted kinase inhibitor cancer therapy.


2015 ◽  
Vol 22 (11) ◽  
pp. 1335-1347 ◽  
Author(s):  
Yan Gao ◽  
Jacson Shen ◽  
Lara Milane ◽  
Francis Hornicek ◽  
Mansoor Amiji ◽  
...  

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Feifei Zhang ◽  
Hui Wang ◽  
Jiang Yu ◽  
Xueqing Yao ◽  
Shibin Yang ◽  
...  

AbstractDe novo and acquired resistance, which are mainly mediated by genetic alterations, are barriers to effective routine chemotherapy. However, the mechanisms underlying gastric cancer (GC) resistance to chemotherapy are still unclear. We showed that the long noncoding RNA CRNDE was related to the chemosensitivity of GC in clinical samples and a PDX model. CRNDE was decreased and inhibited autophagy flux in chemoresistant GC cells. CRNDE directly bound to splicing protein SRSF6 to reduce its protein stability and thus regulate alternative splicing (AS) events. We determined that SRSF6 regulated the PICALM exon 14 skip splice variant and triggered a significant S-to-L isoform switch, which contributed to the expression of the long isoform of PICALM (encoding PICALML). Collectively, our findings reveal the key role of CRNDE in autophagy regulation, highlighting the significance of CRNDE as a potential prognostic marker and therapeutic target against chemoresistance in GC.


Nanoscale ◽  
2019 ◽  
Vol 11 (41) ◽  
pp. 19520-19528 ◽  
Author(s):  
Pengying Wu ◽  
Dongtao Yin ◽  
Jiaming Liu ◽  
Huige Zhou ◽  
Mengyu Guo ◽  
...  

A cancer cell membrane-based biomimetic strategy was developed by loading doxorubicin and icotinib to overcome drug-resistance of EGFR-mutation lung cancer.


2021 ◽  
Vol 17 (1) ◽  
pp. 104-120
Author(s):  
N. Ivanenko

Relevance. Treatment of solid tumors and biofilm-derived infections face a common problem: drugs often fail to reach and kill cancer cells and microbial pathogens because of local microenvironment heterogeneities. There are remarkable challenges for current and prospective anticancer and antibiofilm agents to target and maintain activity in the microenvironments where cancer cells and microbial pathogens survive and cause the onset of disease. Bacterial infections in cancer formation will increase in the coming years. Collection of approaches such as ROS modulation in cells, the tumor is promoted by microbe’s inflammation can be a strategy to target cancer and bacteria. Besides that, bacteria may take the advantage of oxygen tension and permissive carbon sources, therefore the tumor microenvironment (TM) becomes a potential refuge for bacteria. It is noteworthy that the relationship between cancer and bacteria is intertwined. Objective: To analyze similarities between biofilm and tumor milieu that is produced against stress conditions and heterogeneous microenvironment for a combination of approaches the bacteriotherapy with chemotherapy which can help in defeating the tumor heterogeneity accompanied with malignancy, drug-resistance, and metastasis. Method: An analytical review of the literature on keywords from the scientometric databases PubMed, Wiley. Results: Bacteria evade antimicrobial treatment is mainly due to persistence that has become dormant during the stationary phase and tolerance. Drug-tolerant persisters and cellular dormancy are crucial in the development of cancer, especially in understanding the development of metastases as a late relapse. Biofilms are formed by groups of cells in different states, growing or non-growing and metabolically active or inactive in variable fractions, depending on maturity and on chemical gradients (O2 and nutrients) of the biofilms producing physiological heterogeneity. Heterogeneity in the microenvironment of cancer can be described as a non-cell autonomous driver of cancer cell diversity; in a highly diverse microenvironment, different cellular phenotypes may be selected for or against in different regions of the tumor. Hypoxia, oxidative stress, and inflammation have been identified as positive regulators of metastatic potential, drug resistance, and tumorigenic properties in cancer. It is proven that, Escherichia coli (E. coli) and life-threatening infectious pathogens such as Staphylococcus aureus (SA) and Mycobacterium tuberculosis (Mtb) are noticeably sensitive to alterations in the intracellular oxidative environment.  An alternative emerging paradigm is that many cancers may be promoted by commensal microbiota, either by translocation and adherence of microbes to cancer cells or by the distant release of inflammation-activating microbial metabolites. Microbial factors such as F. nucleatum, B. fragilis, and Enterobacteriaceae members may contribute to disease onset in patients with a hereditary form of colorectal cancer (CRC); familial adenomatous polyposis (FAP). These findings are linked with the creation of new biomarkers and therapy for identifying and treating biofilm-associated cancers.  Currently,  about 20% of neoplasms globally can be caused by infections, with  approximately 1.2 million cases annually. Several antineoplastic drugs that exhibited activity against S. mutans, including tamoxifen, doxorubicin, and ponatinib, also possessed activity against other Gram-positive bacteria. Drug repurposing, also known as repositioning, has gained momentum, mostly due to its advantages over de novo drug discovery, including reduced risk to patients due to previously documented clinical trials, lower drug development costs, and faster benchtop-to-clinic transition. Although many bacteria are carcinogens and tumor promoters, some have shown great potential towards cancer therapy. Several species of bacteria have shown an impressive power to penetrate and colonize solid tumors, which has mainly led to neoplasm slower growth and   tumor clearance.  Different strains of Clostridia, Lactococcus, Bifidobacteria, Shigella, Vibrio, Listeria, Escherichia, and Salmonella have been evaluated against cancer in animal models.  Conclusion. Cancer is a multifactorial disease and the use of bacteria for cancer therapy as an immunostimulatory agent or as a vector for carrying the therapeutic cargo is a promising treatment method. Therefore, the world has turned to an alternative solution, which is the use of genetically engineered microorganisms; thus, the use of living bacteria targeting cancerous cells is the unique option to overcome these challenges. Bacterial therapies, whether used alone or combination with chemotherapy, give a positive effect to treat multiple conditions of cancer.


Gene ◽  
2019 ◽  
Vol 714 ◽  
pp. 143972 ◽  
Author(s):  
Sanaz Naghizadeh ◽  
Ali Mohammadi ◽  
Behzad Baradaran ◽  
Behzad Mansoori

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Zuan-Fu Lim ◽  
Patrick C. Ma

AbstractThe biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8559-8559
Author(s):  
Naoki Furuya ◽  
Shigeki Umemura ◽  
Hibiki Udagawa ◽  
Tadasuke Shimokawaji ◽  
Takashi Seto ◽  
...  

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.


2016 ◽  
Vol 52 (18) ◽  
pp. 3631-3634 ◽  
Author(s):  
Ying Tang ◽  
Zhan Wu ◽  
Chong-Hua Zhang ◽  
Xiao-Li Zhang ◽  
Jian-Hui Jiang

An activatable theranostic approach based on self-assembled peptide nanostructures with surface-displayed activatable cytotoxic agents for targeted cancer therapy was developed.


Sign in / Sign up

Export Citation Format

Share Document