scholarly journals Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer

2017 ◽  
Author(s):  
Andrew D. Jenks ◽  
Simon Vyse ◽  
Jocelyn P. Wong ◽  
Deborah Keller ◽  
Tom Burgoyne ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Primary Cilia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Human Cancer ◽  
Structural Features ◽  
Resistance Mechanisms ◽  
Pathway Activation ◽  
Inhibitor Resistance

AbstractPrimary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired andde novoresistance to a variety of kinase inhibitors, and found that in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in cilia length seem to be linked to the lack of recruitment of Kif7 and IFT81 to cilia tips, and result in enhanced hedgehog pathway activation. Notably, Kif7 knockdown is sufficient to confer drug resistance in drug sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. The identification of a broad mechanism of pathway-unbiased drug resistance, represents a major advancement in oncology, and helps define a specific and important role for cilia in human cancer.

scholarly journals Targeting the ERK Signaling Pathway in Melanoma

2019 ◽  
Vol 20 (6) ◽  
pp. 1483 ◽  
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.

scholarly journals Profiling of the drug resistance of thousands of Src tyrosine kinase mutants uncovers a regulatory network that couples autoinhibition to the dynamics of the catalytic domain

2021 ◽  
Author(s):  
Sujata Chakraborty ◽  
Ethan Ahler ◽  
Jessica J. Simon ◽  
Linglan Fang ◽  
Zachary E. Potter ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Protein Kinase Inhibitors ◽  
Resistance Mutations ◽  
Src Tyrosine Kinase ◽  
Inhibitor Resistance

SUMMARYProtein kinase inhibitors are effective cancer therapies, but acquired resistance often limits clinical efficacy. Despite the cataloguing of numerous resistance mutations with model studies and in the clinic, we still lack a comprehensive understanding of kinase inhibitor resistance. Here, we measured the resistance of thousands of Src tyrosine kinase mutants to a panel of ATP-competitive inhibitors. We found that ATP-competitive inhibitor resistance mutations are distributed throughout Src’s catalytic domain. In addition to inhibitor contact residues, residues that participate in regulating Src’s phosphotransferase activity were prone to the development of resistance. Unexpectedly, a resistance-prone cluster of residues that are on the top face of the N-terminal lobe of the catalytic domain contributes to Src autoinhibition by reducing the dynamics of the catalytic domain, and mutations in this cluster led to resistance by lowering inhibitor affinity and promoting kinase hyperactivation. Together, our studies demonstrate how comprehensive profiling of drug resistance can be used to understand potential resistance pathways and uncover new mechanisms of kinase regulation.

scholarly journals Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jean M Mulcahy Levy ◽  
Shadi Zahedi ◽  
Andrea M Griesinger ◽  
Andrew Morin ◽  
Kurtis D Davies ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Braf Inhibitor ◽  
Pediatric Brain Tumors ◽  
Resistance Mechanisms ◽  
Cancer Therapies ◽  
Clinical Responses ◽  
Inhibitor Resistance ◽  
Autophagy Inhibition

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors.

scholarly journals Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer

Cell Reports ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 3042-3055 ◽  
Author(s):  
Andrew D. Jenks ◽  
Simon Vyse ◽  
Jocelyn P. Wong ◽  
Eleftherios Kostaras ◽  
Deborah Keller ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Kinase Inhibitor ◽  
Resistance Mechanisms ◽  
Inhibitor Resistance

scholarly journals Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

2018 ◽  
Vol 62 (4) ◽  
pp. 583-593 ◽  
Author(s):  
Peter T. Harrison ◽  
Paul H. Huang
Keyword(s):  
Drug Resistance ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Effective Means ◽  
Deep Understanding ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Precision Oncology ◽  
First Line ◽  
Clinical Responses

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.

Bortezomib Has No. Ex Vivo Activity in Chronic Myeloid Leukemia: Individual Tumor Response Testing Comparative Study in Pediatric and Adult Acute and Chronic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4257-4257
Author(s):  
Krzysztof Czyzewski ◽  
Lidia Gil ◽  
Beata Kolodziej ◽  
Beata Rafinska ◽  
Krzysztof Lewandowski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Advanced Disease ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Chemotherapy Resistance ◽  
Kinase Domain ◽  
Pediatric Leukemia ◽  
Pediatric Aml

Abstract Abstract 4257 Background Resistance to imatinib is one of the most important issues in treatment of CML. Proteasome inhibitor, bortezomib, is known to be effective in therapy of various neoplasms. Preclinical studies demonstrate the ability of bortezomib in chemosensitization and overcoming of chemotherapy resistance. Objective Analysis of ex vivo drug resistance to bortezomib and another 23 drugs including tyrosine kinase inhibitors (TKI) in CML, in comparison to acute adult and pediatric leukemia. Material and methods A total number of 241 patients entered the study, including: 106 Ph(-)ALL and 53 AML children (age 0.1-18, median 7 years) and 46 AML and 36 CML adults (age 18-69, median 41 years). All children were diagnosed as de novo leukemia, AML adults as de novo (n=20) or relapsed/refractory (n=26). Due to similar drug sensitivity, all adult AML patients were pooled into one group (Gil et al, Anticancer Res, 2007;27:4021). Among CML patients 19 had advanced disease; 16 were resistant to imatinib and 6 had ABL-kinase domain mutations (M244V, E255K, Y253H, M351T and 2 with F317L). Ex vivo drug resistance profile was studied by the MTT assay with the use of following drugs: prednisolone, vincristine, idarubicin, daunorubicin, doxorubicin, mitoxantrone, etoposide, L-asparaginase, melphalan, cytarabine, fludarabine, cladribine, thiotepa, treosulfan, 4-HOO-cyclophosphamide, thioguanine, bortezomib, topotecan, clofarabine and busulfan. CML patients were also tested for sensitivity to TKI: imatinib, dasatinib and nilotinib. Results CML cells were more resistant than AML blasts to following drugs: prednisolone (1.5-fold; p=0.037), vincristine (2.3-fold; p=0.004), doxorubicin (>6.9-fold; p<0.001), etoposide (7.4-fold; p<0.001), melphalan (5.9-fold; p=0.001), cytarabine (12.5-fold; p=0.005), fludarabine (2.6-fold; p=0.008), thiotepa (5.4-fold: p=0.001), 4-HOO-cyclophosphamide (2.3-fold; p=0.015), thioguanine (>4-fold; p<0.001), bortezomib (6.2-fold; p<0.001), topotecan (20-fold; p<0.001), and clofarabine (50-fold; p<0.001). No differences in sensitivity were found for idarubicin, daunorubicin, mitoxantrone, L-asparaginase, cladribine, and treosulfan, while CML cells were 2-fold more sensitive to busulfan (p=0.035). Adult and pediatric AML samples did not differ significantly in ex vivo drug resistance to all tested drugs. Pediatric AML samples were more resistant than pediatric ALL samples to most of tested drugs, however they had comparable sensitivity to cytarabine, thioguanine, bortezomib, and clofarabine. CML patients with mutation had higher ex vivo resistance to: vincristine (3.3-fold; p=0.044), idarubicin (7.9-fold; p=0.031), thiotepa (13.7-fold; p=0.044), and busulfan (21.6-fold; p=0.024). No significant differences were observed with respect to other drugs, including all 3 TKI's. CML patients resistant to imatinib had higher ex vivo resistance to: vincristine (2.5-fold; p=0.016), daunorubicin (3.1-fold; p=0.011), etoposide (2.2-fold; p=0.031), and busulfan (4.5-fold; p=0.032). No significant differences were observed in respect to other drugs, including all 3 TKI's. No significant differences were observed between CML patients with non-advanced and advanced disease to all tested drugs, including TKI's. Conclusions CML cells are ex vivo more resistant to most drugs than acute leukemia blasts. Bortezomib alone has no ex vivo activity in CML patients. No differences between CML subgroups in sensitivity to 3 various TKI was detected. These findings require further investigations. Acknowledgments This study was supported by grants: EC 2008/2009 ZPORR SPS.IV-3040-UE/217/2009; EFS 9/9/POKL/4.4.1/2008; UMK 09/2009 and MNiSW N407 078 32/2964. Disclosures: No relevant conflicts of interest to declare.

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

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2536-2536 ◽  
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.

Anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 60-60
Author(s):  
Steven Brad Maron ◽  
Lindsay Alpert ◽  
David Xu ◽  
Rachel Rendak ◽  
Emily O'Day ◽  
...  
Keyword(s):  
De Novo ◽  
Locally Advanced ◽  
Stage Iv ◽  
Response Duration ◽  
Resistance Mechanisms ◽  
Post Treatment ◽  
Phase Iii ◽  
Pathway Activation ◽  
Gastroesophageal Adenocarcinoma ◽  
Next Generation Sequencing Ngs

60 Background: Gastroesophageal cancer (GEC) is a global health problem. Multiple phase III anti-EGFR trials of unselected metastatic GEC patients (pts) were negative, yet subset analyses suggested potential benefit in pts with EGFR amplification (amp). We sought to quantify the incidence of EGFR amp in metastatic/recurrent GEC pts compared to the locally advanced TCGA rate, treat them with EGFR antagonists, quantify response/duration, and assess for mechanisms of action and resistance (MOA, MOR). Methods: 106 stage IV GEC pts in any therapy (tx) line (L) were prospectively screened for EGFR amp between 9/1/14-8/31/16 at a single site using tumor next generation sequencing (NGS). EGFR amp samples were then assessed by FISH, immunohistochemistry (IHC) and mass spectroscopy (MS) to confirm. Pts received 1L ABT-806 (1/4) or 2L+ cetux (3/4) monoclonal anti-EGFR antibodies, in combination with chemotherapy if 1L or 2L (2/4), or as monotherapy for 3L+ (2/4). Pts were followed for response (ORR) and disease control (DCR). Pre and post-treatment NGS, serial ctDNA, and EGFR/PD-L1 FISH/IHC/MS were obtained to monitor for MOA and MOR to tx. Results: Six (5.7%) pts harbored EGFR amp tumors with copies/cell ranging 54-167. Four eligible pts received >1 dose of tx with monoclonal anti-EGFR therapy: 1 FOLFOX-ABT-806 (1L), 1 FOLFIRI-cetux (2L), and 2 cetux alone (3L, 4L); ORR was 100% (4/4) by RECIST, respectively (-70%, -65%, -77%, -43%). All 3 cetux treated pts developed classic rash, which disappeared when/if progression (2/3). The 4-month DCR was 75% (3/4). No pts showed PD-L1 staining pre/post therapy. Upon progression, the 2L pt acquired de novo PTEN exon 6 deletion after 10 months, while basal NRAS mutated and HER2 amp ctDNA clones had expanded in the 4L pt after 4 months of monotherapy. Conclusions: EGFR amp incidence was similar to TCGA. Despite large negative trials with EGFR antagonists for GEC, EGFR amp predicted benefit (100%) from anti-EGFR tx, including monotherapy in 50%, albeit until various resistance mechanisms emerged, including HER2, RAS, and PTEN/AKT pathway activation. No PD-L1 expression was observed pre/post treatment, consistent with our previous data showing that EGFR-amplified cases trend towards a ‘non-T cell-inflamed’ phenotype. Clinical trial information: NCT01416714 / NCT02213289.

scholarly journals Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin.

1994 ◽  
Vol 127 (3) ◽  
pp. 859-866 ◽  
Author(s):  
R L Klemke ◽  
M Yebra ◽  
E M Bayna ◽  
D A Cheresh
Keyword(s):  
Cell Migration ◽  
Tyrosine Kinase ◽  
Cell Motility ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Pkc Activation

FG human pancreatic carcinoma cells adhere to vitronectin using integrin alpha v beta 5 yet are unable to migrate on this ligand whereas they readily migrate on collagen in an alpha 2 beta 1-dependent manner. We report here that epidermal growth factor receptor (EGFR) activation leads to de novo alpha v beta 5-dependent FG cell migration on vitronectin. The EGFR specific tyrosine kinase inhibitor tyrphostin 25 selectively prevents EGFR autophosphorylation thereby preventing the EGF-induced FG cell migration response on vitronectin without affecting constitutive migration on collagen. Protein kinase C (PKC) activation also leads to alpha v beta 5-directed motility on vitronectin; however, this is not blocked by tyrosine kinase inhibitors. In this case, PKC activation appears to be associated with and downstream of EGFR signaling since calphostin C, an inhibitor of PKC, blocks FG cell migration on vitronectin induced by either PKC or EGF. These findings represent the first report implicating a receptor tyrosine kinase in a specific integrin mediated cell motility event independent of adhesion.

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