Copy number alterations disrupt mitochondrial metabolism.

Focal or arm-level amplification of the oncogene NKX2-1 (chr14q13) and/or loss of heterozygosity at chr14q occurs in 12-53% of lung cancers, and there are currently no molecularly targeted small molecule therapeutics for these alterations. We have recently developed novel compounds targeting the mitochondrial insertase OXA1L, encoded adjacent to NKX2-1 at chr14q11, which is collaterally amplified or deleted along with NKX2-1 across ~10% of samples from The Cancer Genome Atlas. Importantly, these compounds are selectively lethal in NKX2-1 amplified human cancer cell lines, owing to partial inhibition of OxPhos and increased OxPhos-coupled de novo pyrimidine biosynthesis. Based on this mechanism, we seek to validate OXA1L as a target in chr14q amplified and deleted cancer cells and animal models, understand additional vulnerabilities associated with altered pyrmidine biosynthes and further establish structure activity reliationships governing OXA1L inhibitor selectivity.

Figure 1: OXA1L Variation in NKX2-1 Amplified Lung Cancers. a, Schematic of the electron transport chain (grey) and the mitochondrial insertase OXA1L (blue) interacting with the mitochondrial ribosome (gold). b, Chromosomal location of OXA1L and NKX2-1 (Top) and scatterplot of NKX2-1 copy number versus OXA1L mRNA expression across TCGA patient samples. c, OXA1L allele frequency and relative potency (Viability) after 72-hour treatment with OXA1L inhibitors across human cancer cell lines. d, Cystal structure (pdb 6Z5M) of mitoribosome (gold) bound OXA1L c-terminus (blue). OXA1L makes direct polar interaction with adenine rRNA (cyan). e, Cell viability after 72-hour treatment with OXA1L inhibitor (blue), 5-Fluoro uracil (gold), or Paclitaxel (red), in isogenic cell lines stabling expressing OXA1L at varying zygosity. f, isogenic cell models of triploid chr14q and diploid lung cancer. Fluorescence in situ hybridization showing chr14q amplification in the same clones shown left.