Exploiting Synthetic Lethality and Network Biology to Overcome EGFR Inhibitor Resistance in Lung Cancer

Vyse, Simon; Howitt, Annie; Huang, Paul H.

doi:10.1016/j.jmb.2017.04.018

Cited by 15 publications

(12 citation statements)

References 127 publications

(143 reference statements)

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“…However efficacy is often short-lived with the majority of patients going on to develop acquired resistance and tumour recurrence after prolonged drug treatment [3] . Studies in cell line models have revealed several major mechanisms of resistance that have been clinically observed, including the acquisition of drug resistant mutations in the target kinase, activation of bypass signalling pathways and phenotypic alterations such as epithelial-mesenchymal-transition (EMT) [3] , [4] , [5] , [6] . These drug resistant cells arise either from selection of pre-existing clones within a heterogeneous tumour cell population or through the adaptation and subsequent evolution of drug-tolerant persister cells [7] , [8] .…”

Section: Introductionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

Vyse

McCarthy

Broncel

et al. 2018

Journal of Proteomics

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Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.SignificancePazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

Vyse

McCarthy

Broncel

et al. 2018

Journal of Proteomics

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“… ( A ) Gatekeeper mutations on BCR–ABL restore kinase activity in the presence of BCR–ABL inhibitors (BCR–ABLi) in chronic myeloid leukaemia (ATP-binding site mutations and T315I enable resistance to first- and second-generation BCR–ABLi respectively) [ 86 ]. ( B ) Amplification of the EML4–ALK fusion restores signalling in the presence of ALK inhibitor (ALKi) crizotinib in NSCLC by increasing levels of active unbound oncogene [ 87 ].…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

Harrison

Huang

2018

Essays in Biochemistry

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Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.

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“…DNMT1 maintains methylation patterns following DNA replication. Combining DNMT1 inhibition and PARP inhibitors cause synthetic lethality (64). PARP inhibition prevents XRCC1 interaction with several DNA repair proteins, including DNMT1 and thereby insufficient organization of base excision repair (64).…”

Section: Synthetic Lethal Gene Partners Based On Chemo Resi Stancerelmentioning

confidence: 99%

“…Combining DNMT1 inhibition and PARP inhibitors cause synthetic lethality (64). PARP inhibition prevents XRCC1 interaction with several DNA repair proteins, including DNMT1 and thereby insufficient organization of base excision repair (64). We can provide chemoresistance or stem cell-related genes for synthetic lethality pairs of PARP inhibitors in CCC.…”

Section: Synthetic Lethal Gene Partners Based On Chemo Resi Stancerelmentioning

confidence: 99%

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

et al. 2017

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Abstract. Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC.

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Exploiting Synthetic Lethality and Network Biology to Overcome EGFR Inhibitor Resistance in Lung Cancer

Cited by 15 publications

References 127 publications

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib

Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

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