A synthetic lethal strategy to target chromosome 8p deleted cancers

In the past years the concept of synthetic lethality, where inhibition of certain gene products can act as specific vulnerabilities for cancer cells with a particular genetic makeup, was proposed to guide new targeted therapies. With this concept in mind, we aimed to identify a specific target for chromosome 8p deletions.

Using large-scale functional-genomic screening data of over 527 well-characterized cancer cell lines, we were able to identify a dependency of chromosome 8p deleted cancer cell lines on Mitoferrin-2 (MFRN2) a mitochondrial iron transporter. Interestingly, we found that Mitoferrin-1 (MFRN1), the paralog of MFRN2, resides on chromosome 8p and is frequently deleted in liver cancer. We found a strong correlation between the cellular dependency on MFRN2 and the MFRN1 expression levels, possibly explaining why MFRN2 is a synthetic lethal target for 8p deletions. Genetic epistasis experiments in human liver cancer cell lines revealed that knockout of MFRN2 alone was accompanied by reduced cell growth only in cell lines with low MFRN1 expression, whereas combined knockout of MFRN2 or MFRN1 led to reduced cell growth irrespective of the MFRN1 levels. Moreover, exogenous re-expression of MFRN1 in cell lines with low - or no endogenous MFRN1 expression rescued the observed phenotype upon MFRN2 knockout. Strikingly, targeting MFRN2 in human HCC xenograft models led to complete tumor regression in MFRN1-depleted cancer cells. Finally, human tissue samples provided evidence that MFRN2 could be a therapeutic target for a synthetic lethal directed therapy in a subset of primary HCC patients with low MFRN1 expression.

Publication History

Article published online:
18 January 2023