By Aaron F. Phillips; Rumin Zhang et al.
Chromosome instability (CIN) is an attribute of cancer cells that has yet to be fully exploited therapeutically, despite its prevalence across many tumor types and lack of occurrence in normal cells. To identify genes uniquely essential to CINhigh cells, we mined the Cancer Dependency map (DepMap) for genes required for proliferation of tumor cell lines with high levels of copy number aberrations, an indicator of CIN. This analysis identified KIF18A, a mitotic kinesin also identified by others as a vulnerability of aneuploid and whole genome doubled cells. Genetic disruption of KIF18A with RNAi confirmed its necessity in CINhigh cells, and these findings translated to in vivo reduction in tumor growth, illustrating the potential of KIF18A as a therapeutic target.Go to the publication
By Rumin Zhang, Derek Cogan, Christina Eng et al.
e15046 Background: KIF18A is a kinesin assisting chromosome congression and alignment during mitosis. It is nonessential in normal, euploid cell division but essential for a subset of aneuploid cancer cells with high chromosomal instability (CIN-high). KIF18A knockdown in these cells leads to mitotic arrest, cytostasis and cell death. As a result, KIF18A is an attractive anticancer target. Methods: Volastra drug discovery efforts identified and validated KIF18A as a promising target using genetic knockdown and pharmacological inhibition with a tool compound. High-throughput screening identified an ATP-noncompetitive hit that was optimized for potency, selectivity, and pharmacokinetic properties. Breadth of efficacy studies against a panel of cancer cell lines were used to formulate responder hypotheses and aid in patient selection. Mechanistic profiling and cell fate determination upon KIF18A inhibition was used to identify target engagement and clinical response biomarkers.Go to the publication
Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors.
By Ramaswamy Govindan, Amanda Rose Townsend, Kathy D. Miller et al.
TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors.Go to the publication
Abstract LB202: Discovery and preclinical characterization of novel small molecule inhibitors of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers.
By Jan Sun; Brain Belmontes; Jodi Moriguchi et al.
KIF18A is a mitotic kinesin that localizes to the plus-end tips of kinetochore microtubule (MT) spindle fibers during metaphase, where it regulates chromosome alignment, and promotes the viability of chromosomally unstable cancer cells. KIF18A is overexpressed in a subset of human cancers, and its elevated expression is associated with tumor aggressiveness. Chromosomal instability (CIN) is a hallmark of human cancers and is caused by persistent errors in chromosome segregation during mitosis. Aggressive types of human cancer such as high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have elevated levels of CIN and frequently harbor alterations in TP53 tumor suppressor gene. These two CIN+ cancer subtypes share molecular similarities but have limited treatment options at present. The rationale of pharmacological inhibition of KIF18A motor activity is to selectively target a tumor-specific mitotic spindle vulnerability in CIN+ cancer cells while largely sparing normal diploid dividing somatic cells.Go to the publication
Abstract 516: Discovery and preclinical characterization of AMG 650, a first-in-class inhibitor of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers.
By Brian Belmontes; Jodi Moriguchi; Grace Chung et al.
Chromosomal instability (CIN) is a hallmark of human cancers and is caused by persistent errors in chromosome segregation during mitosis. Aggressive types of human cancer such as high-grade serous ovarian cancer and triple-negative breast cancer have elevated levels of CIN and frequently harbor TP53 gene alterations and are poorly served by current treatment options. These two CIN+ cancer types also share mutually exclusive genetic alterations in BRCA1 and CCNE1 cancer genes. KIF18A is a mitotic kinesin motor protein that localizes to the plus-end tips of kinetochore microtubule (MT) spindle fibers, where it regulates chromosome alignment during cell division. KIF18A is overexpressed in a subset of human cancers, and its elevated expression is associated with tumor aggressiveness. Recent reports provide compelling evidence that genetic ablation of KIF18A reduced the viability of CIN cancer cells (Marquis et al. Nature Com 2021, Quinton et al. Nature 2021, Cohen-Sharir et al. Nature 2021).Go to the publication
Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe
By Nuria A. Tamayo*, Matthew P. Bourbeau, Jennifer R. Allen et al.
Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting of CIN-associated vulnerabilities is an emerging therapeutic strategy in drug development. KIF18A, a mitotic kinesin, has been shown to play a role in maintaining bipolar spindle integrity and promotes viability of CIN cancer cells. To explore the potential of KIF18A, a series of inhibitors was identified. Optimization of an initial hit led to the discovery of analogues that could be used as chemical probes to interrogate the role of KIF18A inhibition. Compounds 23 and 24 caused significant mitotic arrest in vivo, which was sustained for 24 h. This would be followed by cell death either in mitosis or in the subsequent interphase. Furthermore, photoaffinity labeling experiments reveal that this series of inhibitors binds at the interface of KIF18A and tubulin. This study represents the first disclosure of KIF18A inhibitors with in vivo activity.Go to the publication
By Jun Li, Melissa J. Hubisz, Ethan M. Earlie et al.
Chromosomal instability (CIN) is a driver of cancer metastasis1,2,3,4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell–cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS–STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.Go to the publication
By Jun Li, Mercedes A. Duran, Ninjit Dhanota et al.
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS–STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti–PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway.Go to the publication
By F Bakhoum, Lewis C Cantley
Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.Go to the publication
By Bakhoum SF, Ngo B, Laughney AM, et al
Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.Go to the publication