Abstract 3965: KIFC1 is a therapeutic target in lung cancers with extra centrosomes
Notice bibliographique
Résumé
Abstract Introduction: Lung cancer is a deadly malignancy and new treatments targeting mechanisms promoting its growth and progression are needed. Genomic instability (GIN) is a recurrent feature of lung tumours that promotes drug resistance and other cancer hallmarks. One mechanism that enables tumour-promoting GIN is centrosome amplification (CA). Centrosomes are organelles involved in chromosome segregation during cell division and two centrosomes in a bipolar arrangement normally ensure equal division of the genome during mitosis. CA, an abnormal increase in centrosome number, is frequently observed in lung and other cancers despite the fact that it can cause lethal multipolar mitotic spindles that potentiate aneuploidy. To mitigate detrimental consequences of CA, cancer cells can cluster extra centrosomes into pseudo-bipolar mitotic spindles. This process is facilitated by a protein called KIFC1 which is upregulated in a large proportion of lung cancers. However, KIFC1’s potential as a therapeutic target in lung cancers with CA has not been explored. Here we investigate the hypothesis that lung cancers with CA are dependent on KIFC1 and sensitive to its inhibition. Methods: Western blotting for KIFC1 and immunofluorescence (IF) for the centrosomal protein, CEP192, were used to measure basal expression and CA, respectively, across a panel of 21 lung adenocarcinoma (LUAD) and 3 non-malignant (NM) cell lines. KIFC1 loss-of-function (LOF) in H1299 and PC9 (LUAD), and BEAS-2B (NM) was achieved using CRISPR/Cas9 and siRNA. In vitro competition assays were done to assess the relative fitness of mCherry-tagged wild-type and GFP-tagged KIFC1-LOF cells in mixed populations over 3-4 cell passages using flow cytometry. CA was potentiated in cells using low doses of the compound, CFI-400945. Clonogenic survival and IF experiments were also done to determine the consequences of KIFC1 LOF. Results: Our findings suggests that basal KIFC1 expression and CA across 21 LUAD cell lines and 3 NM controls are variable. However, we observed a positive correlation (R2 = 0.52, p = 0.01) between KIFC1 expression and CA in LUAD lines. Competition assays revealed that KIFC1 LOF sensitizes LUAD cells with high KIFC1 expression, but not LUAD with low KIFC1 expression or NM cells, to pharmacologically-induced CA. Complementary siRNA experiments confirmed that KIFC1 LOF impairs the survival of cells with CA. Finally, we found that KIFC1 LOF was associated with an increase in multi-polar spindles. Conclusion: These findings support our hypothesis that LUAD with CA are dependent on KIFC1. We suspect its role in centrosome clustering explains this phenotype. Ongoing work is focused on validating these observations in additional models and clinical tumours to confirm its therapeutic potential in LUAD with CA, since combining KIFC1 inhibition with standard of care therapies that induce CA (eg. cisplatin, radiation) could represent an effective therapeutic strategy. Citation Format: Christopher Z. Zhang, Benson Z. Wu, Yin Fang Wu, Caterina di Ciano-Oliveira, Ju-Yoon Yoon, Tak W. Mak, David W. Cescon, Kelsie L. Thu. KIFC1 is a therapeutic target in lung cancers with extra centrosomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3965.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».