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

Abstract

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 promotes tumor development and progression by inducing genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. CA leads to the formation of multipolar mitotic spindles that can cause lethal chromosome segregation errors. To sustain the benefits of CA by mitigating its consequences, malignant cells are dependent on adaptive mechanisms that represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with tumor genomic analyses, we identified the motor protein KIFC1, also known as HSET, as a putative vulnerability specifically in lung adenocarcinoma (LUAD) with CA. KIFC1 expression was positively correlated with CA in LUAD and associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells with high basal KIFC1 expression to potentiation of CA, which was associated with a diminished ability 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 LUAD with CA by forcing cells to divide with multipolar spindles, rationalizing further studies to investigate its therapeutic potential.