An attractive approach to developing new cancer treatments is by exploiting synthetic lethality to selectively target tumor cells. Synthetic lethality occurs when simultaneous disruption of two genes causes cell death, but individual perturbations of each gene does not. This is a powerful concept in cancer treatment, as almost all cancers contain inactivated genes that persist in healthy cells; finding synthetic lethal partners for these mutated genes is a strategy to target tumors while sparing normal tissue. Indeed, this approach to cancer therapy has yielded success in the development of PARP inhibitors in BRCA1, BRCA2, or PALB2-deficient cancers. However, finding successful examples more broadly in other systems has remained more elusive. In this ASPIRE award, Stephen Jackson and his team will use sophisticated models to screen for synthetic lethal targets in two specific genetic backgrounds found in cancerous tissue.
In their first project, they will screen for synthetic lethal targets of CDKN2A, a tumor suppressor that is frequently mutated in patients predisposed to familial melanoma, pancreatic cancer, head and neck cancer, and sporadic cancers. Current interventions for patients with mutated CDKN2A are only moderately effective. Jackson and team will use CRISPR/Cas9 technology to screen for genes that may drive synthetic lethality in patients with CDKN2A-deficient cells. They plan to screen “already drugged” targets to identify genes that, when inactivated, selectively inhibit proliferation or viability of CDKN2A-deficient cells.
In parallel, they will examine ways of overcoming tumor resistance to ATR inhibition. From previous studies harnessing the synthetic lethality approach, it was found that cancer cells with defects in the DNA damage response pathway exhibit genetic instability, and in this genetic background inhibition of the ATR kinase causes cell death. Unfortunately, eventual resistance to these inhibitors often arises, circumventing the initial synthetical lethal interaction. Previously, Jackson and coworkers identified that the loss of either of two genes, Cyclin C or CDK8, confers resistance to ATR inhibitors (ATRi). They hypothesize that the resistance mechanism of down-regulating Cyclin C/CDK8 will provide new therapeutic vulnerabilities against the cancer cell. Using CRISPR/Cas9 technology, they will screen for dependency on other pathways in Cyclin C knockout cells treated with ATRi.
Both of these projects will open up avenues for further studies into mechanisms of new cancer targets with therapeutic potential. The studies may also provide novel biomarkers, enable patient stratification and monitoring, and create new tools to predict a patient’s response to treatment.
Awwad SW, Serrano-Benitez A, Thomas JC, Gupta V, Jackson SP. Revolutionizing DNA repair research and cancer therapy with CRISPR-Cas screens. Nat Rev Mol Cell Biol. 2023.