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.

Efficacy of tyrosine kinase inhibitors (TKIs) based on the ALK resistance mutations on amplicon-based liquid biopsy in ALK positive non-small cell lung cancer (NSCLC) patients (pts).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3055-3055
Author(s):  
Laura Mezquita ◽  
Aurélie Swalduz ◽  
Cecile Jovelet ◽  
Sandra Ortiz-Cuaran ◽  
David Planchard ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Next Generation ◽  
Resistance Mutations ◽  
Durable Response ◽  
Free Survival ◽  
Alk Positive ◽  
Nsclc Patients

3055 Background: Acquired ALK resistance mutations (mut.) are the main mechanism of tyrosine kinase inhibitor (TKI) resistance (30-50%). While next-generation TKIs are more active on mut. than earlier TKIs, compound ALK resistance are associated with failure to next-generation TKIs. We evaluated the clinical utility of detecting ALK resistance mutations in blood to predict TKI efficacy. Methods: ALK positive advanced NSCLC pts were prospectively enrolled between Oct. 2015 and Aug. 2018 in 8 French institutions. Prospective samples were collected; ctDNA was analyzed by amplicon-based Inivata InVisionFirst-Lung. Results: A total of 101 pts with advanced ALK positive NSCLC were enrolled and 328 samples collected. In samples collected at TKI failure (N=74), we detected 9 single and 7 complex (≥2) ALK resistance mut. (22%), associated with EML4-ALK variant 3 (38%) vs. variant 2 (13%) vs. variant 1 (none); 30% had other somatic mut. (mainly TP53 and KRAS, PI3KCA, MET, etc.). No mutations were detected in 48% of samples (ctDNA neg). ALK mut. were more frequent after 2nd/3rd generation TKI (43% post-lorlatinib (7), 29% post-2nd gen. (31), 11% post-crizotinib (36)). ALKG1202R was the most common, as single (n=3) or complex mut. (n=4). The median overall survival (mOS) was 100.4 mo. (95% CI 41.9-158.9) and the median progression free-survival (mPFS) to subsequent line was 2.8 mo. (0.7-4.9). Patients with ctDNA neg had mOS of 105 mo. (39.3-172.1) vs. 58.5 mo. (33.1-84.0) if ≥1 ALK mut. vs. 44.1 mo. (20.0-68.2) if others ( P=0.001). Pts with the complex ALK mut. had worse OS compared to singles ALK mut. (mOS 26.9 mo. vs. 58.5 mo., P=0.001); ALK complex mut. were associated with poor efficacy to subsequent therapy (PFS <3 mo. in 57%; no cases with PFS >6 mo.) vs. single mut., with longer PFS (PFS >6 mo. in 56%). Detectable ALKG1202R mut. were associated with shorter median OS (58.3 mo.; 7.9-109.1) vs. overall population; 86% of cases developed rapid PD (PFS <3mo.) to subsequent therapy with only one durable response to lorlatinib (PFS >6mo.). Conclusions: The absence of ctDNA mutations at TKI failure was associated with prolonged OS, whereas complex ALK mutations at TKI failure may predict resistance to subsequent therapy. Larger and specifically designed studies should be performed to validate these findings.

Generation of Specific Resistance Profiles in FLT3-ITD and FIP1L1-PDGFRalpha towards Specifically Acting Tyrosine Kinase Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1376-1376
Author(s):  
Nikolas von Bubnoff ◽  
Silvia Thoene ◽  
Sivahari P. Gorantla ◽  
Jana Saenger ◽  
Christian Peschel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Resistance Mutations ◽  
Abl Kinase ◽  
Mechanism Of Resistance

Abstract BCR-ABL kinase domain mutations constitute the major mechanism of resistance in patients with chronic myelogenous leukemia treated with the ABL kinase inhibitor imatinib. Mutations causing resistance to therapeutic kinase inhibition were also identified in other target kinases in various malignant diseases, such as FLT3-ITD in acute myelogenous leukemia, cKit in gastrointestinal stromal tumors, EGFR in patients with lung cancer, and FIP1L1-PDGFRalpha in hypereosinophilic syndrome. Thus, mutations in kinase domains seem to be a general mechanism of resistance to therapeutically applicated tyrosine kinase inhibitors. We recently developed a cell-based screening strategy that allows one to predict the pattern and relative abundance of BCR-ABL resistance mutations emerging in the presence of imatinib, and the novel ABL kinase inhibitor AMN107 (nilotinib). We therefore intended to determine, if this method would also allow the generation of resistant cell clones with other oncogeneic tyrosine kinases as targets in the presence of specifically acting kinase inhibitors. When FLT3-ITD and su5614 were used as drug/target combination in our cell-based method, the frequency of resistant clones in the presence of su5614 at 10 times the IC50 was 0.17 per million cells. In 40 per cent of resistant clones, point mutations were detected leading to amino acid exchanges within the FLT3-ITD split kinase domain. The yield of resistant clones was increased by the factor of 14 to 2.37 per million cells by adding ethyl-nitrosourea (ENU), a potent inducer of point mutations. Also, the proportion of mutant clones increased from 40 to 74 per cent. In 83 mutant clones that were examined so far, we detected eight exchanges affecting kinase domain two (TK2) of the split kinase domain within or shortly behind the FLT3-ITD activation loop (A-loop). We did not detect exchanges affecting TK1. We next examined whether resistant clones would also come up with FIP1L1-PDGFRalpha-transformed cells in the presence of imatinib. Again, the yield of resistant clones increased when cells were pretreated with ENU, and a proportion of resistant clones contained mutations in the FIP1L1-PDGFRalpha kinase domain, affecting the nucleotide-binding loop (P-loop) and A-loop. We conclude that cell-based resistance screening is a simple and powerful tool that allows prediction of resistance mutations towards kinase inhibitors in various relevant oncogeneic kinases.

scholarly journals An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance

2021 ◽  
Author(s):  
Adela Patcas ◽  
Ana Florica Chis ◽  
Claudia Florentina Militaru ◽  
Roxana Ioana Bordea ◽  
Ruxandra Rajnoveanu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Practice ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Resistance Mutations ◽  
Mechanisms Of Resistance ◽  
Medical Databases ◽  
Anaplastic Lymphoma

Implementation of precision medicine in lung cancer has benefited from intense research in the past years, developing subsequently an improved quality of life and increased overall survival of the patients. Targeted therapy has become one of the most important therapeutic innovations for the non-small cell lung cancer (NSCLC) category with anaplastic lymphoma kinase (ALK) gene rearrangement. The aim of this review is to provide a through overview of the main molecules of ALK tyrosine kinase inhibitors (TKI) with their general and particular mechanisms of resistance, the main methods of ALK gene detection, each with advantages and limits and the future perspectives currently under research which try to overcome the mechanisms of resistance. We have used two of the most reliable medical databases EMBASE and PubMed to properly select the latest and the most relevant articles for this topic. Encouraged by the promising results, the clinical practice was enriched by the approval of tyrosine kinase inhibitor molecules, three generations being developed, each one with more powerful agents than the previous ones. Unfortunately, the resistance to TKI eventually occurs and it may be induced by several mechanisms, either known or unknown. Crizotinib was the most intensely studied TKI , becoming the first molecule approved into clinical practice and although four other drugs have been broadly used (alectinib, ceritinib, brigatinib and lorlatinib) it seems that even the most recently developed one remains imperfect due to the resistance mutations that developed. There are two types of resistance generally described for the entire class and for the particular drugs, but half of them remain unknown Read more in PDF.

scholarly journals A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias

Blood ◽  
2014 ◽  
Vol 123 (21) ◽  
pp. 3296-3304 ◽  
Author(s):  
Leonid Dubrovsky ◽  
Dmitry Pankov ◽  
Elliott Joseph Brea ◽  
Tao Dao ◽  
Andrew Scott ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
T Cell Receptor ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cell Receptor ◽  
Murine Models ◽  
Key Points ◽  
Inhibitor Resistance

Key Points This study shows the effective anticancer activity of a T-cell receptor mimic antibody targeting WT1 in resistant human Ph+ ALL. In combination with tyrosine kinase inhibitors, ESKM can result in cure of Ph+ ALL in murine models.

scholarly journals Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 152 ◽  
Author(s):  
Cristian Tomasetti ◽  
George D Demetri ◽  
Giovanni Parmigiani
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Genetic Changes ◽  
Stromal Tumors ◽  
Mathematical Formulas ◽  
Inhibitor Resistance

Background: Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes.Methods and results: By combining clinical and experimental observations with mathematical formulas we estimate that, in advanced GIST, the genetic changes responsible for resistance are generally already present at disease detection.Conclusion: This result has relevant clinical implications by providing support for the exploration of combination therapies.

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.

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