Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification

Centrosome amplification (CA), an abnormal increase in the number of centrosomes in the cell, is a recurrent phenomenon in lung and other malignancies. Although CA contributes to tumor development and progression by promoting genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. The presence of extra centrosomes leads to the formation of multipolar mitotic spindles prone to causing lethal chromosome segregation errors during cell division. To sustain the benefits of CA, malignant cells are dependent on adaptive mechanisms to mitigate its detrimental consequences, and these mechanisms represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with analyses of tumor genomic data, we identified the motor protein KIFC1 as a putative vulnerability specifically in lung cancers with CA. KIFC1 expression was positively correlated with CA in lung adenocarcinoma (LUAD) cell lines and with a gene expression signature predictive of CA in LUAD tumor tissues. High KIFC1 expression was associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells to potentiation of CA and sensitization was associated with a diminished ability of KIFC1-depleted cells to cluster extra centrosomes into pseudo-bipolar mitotic spindles. Our work suggests that KIFC1 inhibition represents a novel approach for potentiating GIN to lethal levels in LC with CA by forcing cells to divide with multipolar spindles, rationalizing the clinical development of KIFC1 inhibitors and further studies to investigate its therapeutic potential. ### Competing Interest Statement Christopher Zhang, Benson Wu, Yin Fang Wu, Caterina di Ciano-Oliveira, Nhu-An Pham, Andrew J. Elia, Raj Chari, Wan L. Lam, Ming S. Tsao, Kelsie L. Thu - none Isabel Soria-Bretones - ISB is currently an employee of Repare Therapeutics Mark Bray - MRB is currently an employee of Treadwell Therapeutics Tak Mak - Owns equity in Treadwell Therapeutics Inc. and Agios Pharmaceuticals and is a consultant for AstraZeneca and Tessa Therapeutics David Cescon - DWC reports consultancy and advisory relationships with AstraZeneca, Daiichi Sankyo, Exact Sciences, Eisai, Gilead, GlaxoSmithKline, Inflex, Inivata/NeoGenomics, Lilly, Merck, Novartis, Pfizer, Roche and Saga; research funding to their institution from AstraZeneca, Guardant Health, Gilead, GlaxoSmithKline, Inivata/NeoGenomics, Knight, Merck, Pfizer, ProteinQure and Roche