scholarly journals Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint

2019 ◽  
Author(s):  
Klaske M. Schukken ◽  
Yi-Chih Lin ◽  
Michael Schubert ◽  
Stephanie F. Preuss ◽  
Judith E. Simon ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Kinase Inhibitor ◽  
Chromosome Instability ◽  
Src Kinase ◽  
Microtubule Dynamics ◽  
Target Cells ◽  
Microtubule Polymerization ◽  
Powerful Means ◽  
Small Molecule Compound ◽  
Microtubule Poisons

AbstractChromosome instability (CIN) and aneuploidy are hallmarks of cancer. As the majority of cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings therefore suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.

scholarly journals Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition

2020 ◽  
Vol 3 (2) ◽  
pp. e201900499 ◽  
Author(s):  
Klaske M Schukken ◽  
Yu-Chih Lin ◽  
Petra L Bakker ◽  
Michael Schubert ◽  
Stephanie F Preuss ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Spindle Assembly ◽  
Microtubule Dynamics ◽  
Target Cells ◽  
Microtubule Polymerization ◽  
Powerful Means ◽  
Small Molecule Compound ◽  
Microtubule Poisons

Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.

scholarly journals TOG–tubulin binding specificity promotes microtubule dynamics and mitotic spindle formation

2017 ◽  
Vol 216 (6) ◽  
pp. 1641-1657 ◽  
Author(s):  
Amy E. Byrnes ◽  
Kevin C. Slep
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Polymerase Activity ◽  
Microtubule Dynamics ◽  
Spindle Formation ◽  
Microtubule Binding ◽  
Microtubule Polymerization ◽  
Tubulin Binding ◽  
Specific Order ◽  
Spindle Function

XMAP215, CLASP, and Crescerin use arrayed tubulin-binding tumor overexpressed gene (TOG) domains to modulate microtubule dynamics. We hypothesized that TOGs have distinct architectures and tubulin-binding properties that underlie each family’s ability to promote microtubule polymerization or pause. As a model, we investigated the pentameric TOG array of a Drosophila melanogaster XMAP215 member, Msps. We found that Msps TOGs have distinct architectures that bind either free or polymerized tubulin, and that a polarized array drives microtubule polymerization. An engineered TOG1-2-5 array fully supported Msps-dependent microtubule polymerase activity. Requisite for this activity was a TOG5-specific N-terminal HEAT repeat that engaged microtubule lattice-incorporated tubulin. TOG5–microtubule binding maintained mitotic spindle formation as deleting or mutating TOG5 compromised spindle architecture and increased the mitotic index. Mad2 knockdown released the spindle assembly checkpoint triggered when TOG5–microtubule binding was compromised, indicating that TOG5 is essential for spindle function. Our results reveal a TOG5-specific role in mitotic fidelity and support our hypothesis that architecturally distinct TOGs arranged in a sequence-specific order underlie TOG array microtubule regulator activity.

scholarly journals A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621

Lung Cancer ◽  
2014 ◽  
Vol 85 (2) ◽  
pp. 245-250 ◽  
Author(s):  
Julian R. Molina ◽  
Nathan R. Foster ◽  
Thanyanan Reungwetwattana ◽  
Garth D. Nelson ◽  
Andrew V. Grainger ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Src Kinase ◽  
Small Cell ◽  
Small Cell Lung ◽  
Extensive Stage

scholarly journals Regulation of Microtubule Dynamics by Bim1 and Bik1, the Budding Yeast Members of the EB1 and CLIP-170 Families of Plus-End Tracking Proteins

2010 ◽  
Vol 21 (12) ◽  
pp. 2013-2023 ◽  
Author(s):  
Kristina A. Blake-Hodek ◽  
Lynne Cassimeris ◽  
Tim C. Huffaker
Keyword(s):  
Budding Yeast ◽  
Family Members ◽  
Microtubule Dynamics ◽  
Microtubule Assembly ◽  
Microtubule Polymerization

Microtubule dynamics are regulated by plus-end tracking proteins (+TIPs), which bind microtubule ends and influence their polymerization properties. In addition to binding microtubules, most +TIPs physically associate with other +TIPs, creating a complex web of interactions. To fully understand how +TIPs regulate microtubule dynamics, it is essential to know the intrinsic biochemical activities of each +TIP and how +TIP interactions affect these activities. Here, we describe the activities of Bim1 and Bik1, two +TIP proteins from budding yeast and members of the EB1 and CLIP-170 families, respectively. We find that purified Bim1 and Bik1 form homodimers that interact with each other to form a tetramer. Bim1 binds along the microtubule lattice but with highest affinity for the microtubule end; however, Bik1 requires Bim1 for localization to the microtubule lattice and end. In vitro microtubule polymerization assays show that Bim1 promotes microtubule assembly, primarily by decreasing the frequency of catastrophes. In contrast, Bik1 inhibits microtubule assembly by slowing growth and, consequently, promoting catastrophes. Interestingly, the Bim1-Bik1 complex affects microtubule dynamics in much the same way as Bim1 alone. These studies reveal new activities for EB1 and CLIP-170 family members and demonstrate how interactions between two +TIP proteins influence their activities.

3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases

2005 ◽  
Vol 13 (15) ◽  
pp. 4704-4712 ◽  
Author(s):  
Ram Thaimattam ◽  
Pankaj R. Daga ◽  
Rahul Banerjee ◽  
Javed Iqbal
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
3D Qsar ◽  
Qsar Studies ◽  
Abl Kinases

scholarly journals A novel Src kinase inhibitor reduces tumour formation in a skin carcinogenesis model

2008 ◽  
Vol 30 (2) ◽  
pp. 249-257 ◽  
Author(s):  
Bryan Serrels ◽  
Alan Serrels ◽  
Susan M. Mason ◽  
Christine Baldeschi ◽  
Gabrielle H. Ashton ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Src Kinase ◽  
Skin Carcinogenesis ◽  
Tumour Formation

scholarly journals Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 548 ◽  
Author(s):  
Patricia Gaule ◽  
Nupur Mukherjee ◽  
Brendan Corkery ◽  
Alex Eustace ◽  
Kathy Gately ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Combined Treatment ◽  
Single Agent ◽  
Src Kinase ◽  
Ic50 Value ◽  
Met Inhibitor ◽  
Dasatinib Treatment

In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC50 value greater than 5 μM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC50 value of 1.4 ± 0.5 µM compared to an IC50 of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC.

Sign in / Sign up

Export Citation Format

Share Document