Synthetic Lethality Pipeline

Overview

Our pipeline in synthetic lethality comprises multiple preclinical programs, complemented by a robust target discovery platform to help identify future synthetic lethality program opportunities. We are pursuing small molecule inhibitors of targets in tumor cells having MTAP gene deletion, which occurs in approximately 15% of all solid tumors, in tumors with genetic mutations in homologous recombination deficiency (HRD), including BRCA mutations which occur, for example, in approximately 14% of ovarian cancer tumors, in tumors with genetic mutations in base excision repair, the prevalence of which is being evaluated in several solid tumors, and in high microsatellite instability (MSI) tumors, present for example, in approximately 15% of colorectal cancer tumors.

MTAP Deletion in Solid Tumors

MTAP-null cells lack the ability to metabolize 5-methylthioadenosine, or MTA, which is an essential step in a biochemical pathway involved in salvaging the metabolite S-adenosyl methionine, or SAM. MTA is a partial inhibitor of the methyltransferase PRMT5, rendering MTAP-null cells more dependent on the activity of PRMT5 and other enzymes in this pathway, such as MAT2A and RIOK1. Several potential targets may be synthetic lethal with MTAP deletion when pharmacologically inhibited.

MTAP deletions are prevalent in approximately 15% of all human tumors across various tumor types. Genetic profiling tests for the deletion of MTAP or for the commonly co-deleted gene CDKN2A are commercially available.

MTAP Gene Deletion Renders Cells More Dependent on Enzymes Such as PRMT5, MAT2A and RIOK1
Prevalence of MTAP Deletions in Selected Indications

Source: TCGA Data in cBioportal

Homologous Recombination Deficiency in Solid Tumors

Genetic mutations in genes involved in homologous recombination deficiency (HRD), including BRCA mutations, are prevalent in various solid tumor indications. Genetic profiling tests for mutations in HRD, such as BRCA1 and BRCA2, are commercially available.

Prevalence of HRD in Solid Tumor Types

Source: Heeke et al., JCO Precis Oncol. Sep 2018

High Microsatellite Instability in Solid Tumors

Microsatellite Instability (MSI) is a change in the DNA content of a tumor cell in which the number of repeats of microsatellites, short repeated sequences of DNA, differ as cells divide. High MSI is present in many solid tumor cancers. Tumors with high MSI are routinely assessed in multiple diagnostic profiling tests.

Prevalence of High MSI Frequency in Solid Tumor Types

Source: JCO Precision Oncology 2017