Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

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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Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽

10.3390/cancers11081197 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1197 ◽

Cited By ~ 24

Author(s):

Zaman ◽

Wu ◽

Bivona

Keyword(s):

Kinase Inhibitors ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Genetic Alterations ◽

Therapeutic Strategies ◽

Wild Type ◽

Braf Mutations ◽

Molecular Alterations ◽

Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

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Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

Journal of Hematology & Oncology ◽

10.1186/s13045-019-0818-2 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 22

Author(s):

Zuan-Fu Lim ◽

Patrick C. Ma

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Targeted Therapy ◽

Minimal Residual Disease ◽

Tumor Heterogeneity ◽

Residual Disease ◽

Resistance Mechanisms ◽

Intratumoral Heterogeneity ◽

Acquired Drug Resistance ◽

Minimal Residual

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.

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Targeting the ERK Signaling Pathway in Melanoma

International Journal of Molecular Sciences ◽

10.3390/ijms20061483 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1483 ◽

Cited By ~ 28

Author(s):

Paola Savoia ◽

Paolo Fava ◽

Filippo Casoni ◽

Ottavio Cremona

Keyword(s):

Drug Resistance ◽

Signaling Pathway ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Mapk Pathway ◽

Clinical Trial Data ◽

Resistance Mechanisms ◽

Additional Advantage ◽

Activating Mutations ◽

Extracellular Signal

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

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Bioactive Compounds from Seaweed with Anti-Leukemic Activity: A Mini-Review on Carotenoids and Phlorotannins

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190311095655 ◽

2020 ◽

Vol 20 (1) ◽

pp. 39-53 ◽

Cited By ~ 1

Author(s):

Tânia P. Almeida ◽

Alice A. Ramos ◽

Joana Ferreira ◽

Amaya Azqueta ◽

Eduardo Rocha

Keyword(s):

Drug Resistance ◽

Bioactive Compounds ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

First Line ◽

In Vivo Models ◽

Few Data

: Chronic Myeloid Leukemia (CML) represents 15-20% of all new cases of leukemia and is characterized by an uncontrolled proliferation of abnormal myeloid cells. Currently, the first-line of treatment involves Tyrosine Kinase Inhibitors (TKIs), which specifically inhibits the activity of the fusion protein BCR-ABL. However, resistance, mainly due to mutations, can occur. In the attempt to find more effective and less toxic therapies, several approaches are taken into consideration such as research of new anti-leukemic drugs and “combination chemotherapy” where different drugs that act by different mechanisms are used. Here, we reviewed the molecular mechanisms of CML, the main mechanisms of drug resistance and current strategies to enhance the therapeutic effect of TKIs in CML. Despite major advances in CML treatment, new, more potent anticancer drugs and with fewer side effects are needed. Marine organisms, and particularly seaweed, have a high diversity of bioactive compounds with some of them having anticancer activity in several in vitro and in vivo models. The state-of-art suggests that their use during cancer treatment may improve the outcome. We reviewed here the yet few data supporting anti-leukemic activity of some carotenoids and phlorotannins in some leukemia models. Also, strategies to overcome drug resistance are discussed, particularly the combination of conventional drugs with natural compounds.

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Pharmacological interactions of TKIs with the P-gp drug transport protein.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2536 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2536-2536 ◽

Cited By ~ 1

Author(s):

Sandra Roche ◽

Kasper Pedersen ◽

Grainne Dunne ◽

Denis Collins ◽

Aoife Devery ◽

...

Keyword(s):

Drug Resistance ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Drug Transport ◽

Kinase Inhibitors ◽

Resistance Mechanisms ◽

Cancer Drug ◽

Clear Understanding ◽

Pharmacological Interactions

2536 Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug transport proteins. P-gp is a transporter with two important roles in cancer drug therapy. If overexpressed in tumour cells it can cause drug resistance. However, P-gp, expressed in tissues as part of normal drug clearance mechanisms, is also involved in termination of drug action. Hence, TKI-mediated interactions with P-gp have significant therapeutic consequences. Methods: P-gp over-expressing cancer cell lines were used to determine the inhibitor or substrate status of tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). Cell proliferation assays in combination with a potent P-gp inhibitor, or P-gp substrate were also employed. Findings were augmented using LC-MS-based quantitation of cellular levels of target drugs. Results: We summarise our findings of four distinct interactions with P-gp among various TKIs. Some agents have little interaction at conventional doses; others can act as P-gp inhibitors without being substrates; substrates without being inhibitors or substrates which also prevent the actions of the transporter.Eachof the investigated TKIs has a distinct relationship with P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is a substrate but not an inhibitor, while pazopanib has little interaction with P-gp. Other agents also have an effect on or are affected by P-gp to varying amounts with some of these interactions likely to be suprapharmacological. Conclusions: P-gp protein has important roles both in resistance and drug toxicology, hence, a clear understanding of the interaction of emerging drugs with this transporter is vital. Agents which are inhibitors of P-gp may have applications in drug resistance circumvention but may also greatly exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; conversely the activity of P-gp substrate TKIs may be reduced by tumour overexpression of the transporter. Hence in vitro screening of TKI-transporter interactions may identify putative TKI resistance mechanisms, help guide the development of combination schedule trials and/or reducing unwanted treatment side effects.

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Meta-analysis of outcomes of VEGF and EGFR targeted biologic therapy in relapsed metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.534 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 534-534 ◽

Cited By ~ 1

Author(s):

David Chan ◽

Eva Segelov ◽

Jeremy David Shapiro ◽

Timothy Jay Price ◽

Christos Stelios Karapetis ◽

...

Keyword(s):

Targeted Therapy ◽

Kinase Inhibitors ◽

Biologic Therapy ◽

Meta Analysis ◽

Progression Free Survival ◽

Biologic Agents ◽

First Line ◽

Grade 3 ◽

Line Setting ◽

The Impact

534 Background: Biologic therapies used in treatment of mCRC are expensive and there is debate about their value. We examined the impact of biologic therapy on overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3/4 toxicity for patients beyond first-line treatment. Methods: MEDLINE, EMBASE, and Cochrane libraries were searched for randomized studies in relapsed mCRC comparing treatment containing targeted therapy to the same treatment without targeted therapy. Biologic agents were classed as: EGFR-inhibitors (EGFR-I), VEGF antibody/trap and VEGFR tyrosine kinase inhibitors (TKI). Only KRAS wild-type patients were included for EGFR-I analysis. Results were aggregated according to standard meta-analytic techniques. Results: 10 studies evaluating 5,847 patients were identified. Considering subgroups and lines, OS and PFS benefit was demonstrated in all groups across all lines except for OS in 2nd line EGFR-I use (which may be due to subsequent crossover). A benefit to ORR was seen with EGFR-I 2nd line (Pooled ORR benefit +24%, Odds Ratio (OR) 4.44, 95% CI 3.20-6.18), EGFR-I 3rd line and beyond (Pooled ORR benefit +16%), VEGF antibody/trap (Pooled ORR benefit +7.2%, OR 2.00, 95% CI 1.57-2.54) and VEGFR TKI (Pooled ORR benefit +1.9%, OR 2.05, 95% CI 1.27-3.30). The risk of grade 3/4 toxicity was greater with the addition of all targeted agents. Conclusions: The use of VEGF and EGFR targeted biologic agents beyond first-line setting in mCRC results in a benefit to OS, PFS and ORR for all agents except for OS benefit with second-line EGFR-I. This benefit comes at the cost of increased toxicity. [Table: see text]

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Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

Cancer Drug Resistance ◽

10.20517/cdr.2021.112 ◽

2022 ◽

Author(s):

Samson Ghilu ◽

Christopher L. Morton ◽

Angelina V. Vaseva ◽

Siyuan Zheng ◽

Raushan T. Kurmasheva ◽

...

Keyword(s):

Drug Resistance ◽

High Risk ◽

Tumor Regression ◽

Population Level ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Tumor Resistance ◽

Intrinsic Resistance ◽

Clinical Resistance

Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431. Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis. Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment. Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a “population” level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent “high-risk” tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

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