Molecular targeted therapeutics as a means of precision oncology has so far almost exclusively focused on oncogenes as drug-targets, leaving the majority of cancer-specific alterations untouched. This includes deletions of tumor suppressor genes, a prototypic event in diverse cancers that is currently therapeutically- inactionable. We have demonstrated that homozygous deletion of tumor suppressor genes can expose cancer- specific therapeutic vulnerabilities. This occurs if the genomic deletion includes neighboring ?passenger? genes with redundant paralogues, in pathways that play essential roles in cellular housekeeping. Cancers that harbor these deletions are subsequently dependent upon these redundant paralogues for viability. The targeting of these vulnerabilities, generated indirectly by collateral proximity to deleted tumor suppressors, has been termed ?collateral lethality.? This method of therapeutic targeting has been successful for deletion of the 1p36 tumor suppressor locus, which includes ENO1, a glycolytic gene that confers collateral lethality upon inhibition of its redundant paralogue ENO2. However, this deletion only occurs in a limited patient population. Here, we seek to apply this model to homozygous deletion of the 10q23 locus harboring the PTEN tumor suppressor gene, which occurs frequently in a wide range of cancers, including Glioblastoma and Melanoma. Deletion of PTEN is associated with poor prognosis, metastasis, and resistance to checkpoint blockade immunotherapy. Although currently therapeutically inactionable, we hypothesize that PTEN deletions can be successfully targeted through the ?collateral lethality? paradigm, as multiple housekeeping genes are collaterally deleted with PTEN. This includes PANK1, which encodes pantothenate kinase (PANK), an enzyme with two redundant paralogues that catalyzes the rate-limiting step in biosynthesis of the biologically essential cofactor Coenzyme A. Knockout mice of any single isoform have been shown to be viable, whereas knockout of Pank1, in combination with either Pank2 or Pank3, has been shown to be lethal early in development. We will determine whether PANK activity is essential for cancer cell viability, and which PANK isoform, if any, can serve as a collateral lethality drug target for PANK1 homozygous deleted tumors. We will profile the biochemical consequences of Coenzyme A depletion in response to PANK ablation, and determine whether IONIS anti-sense oligonucleotides against PANK paralogues can be utilized as molecular targeted therapeutics for PANK1 homozygously deleted tumors. Successful execution of this proposal stands to demonstrate the utility of collateral lethality beyond a niche-application. Given the large number of collaterally-deleted genes in the cancer genome, this would greatly expand what may be considered therapeutically-actionable genetic alterations, dramatically increasing the scope and utility of molecular targeted therapeutics in precision oncology.
Use of the novel therapeutic strategy of ?collateral lethality? in response to tumor suppressor deletion is expected to generate an array of cancer drug-targets that have previously been inaccessible to molecular therapeutics. Regardless of the extent of malignancy, transformation and signaling-pathway dysregulation, all normal and cancer cells rely on basic ?housekeeping? functions to remain alive. Unlike molecular therapeutics aimed at activated oncogenes, collateral lethality selectively inhibits these basic functions, providing fresh therapeutic options to patients with even the most highly advanced and metastatic cancers.
