Cancer Textbook: 1

I. Tumor intrinsic targets

Oncogene Addiction

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Tumor Suppressor Rescue

Loss of tumor suppressor genes is common in cancer, and several methods of targeting these loss-of-function events are currently under development. For example, loss-of-function mutations in the CBL ubiquitin ligase lead to increased signaling through several tyrosine kinases. Likewise, mutations in PTEN, which inactivate its phosphatase activity, increase PI3K signaling. In these cases, pharmacological targeting of the activated pathway, rather than the abnormal protein, is very promising. Targeting the TP53 mutant with drugs that stabilize 3D structure and restore its normal function has also emerged as a promising approach (Levine, 2019). More generally, variant-oriented protein-protein interaction touchscreens have identified small molecules that restore interactions lost following tumor suppressor mutations (Tang et al., 2020). This study identified a bisindolylmaleimide derivative that restored the interaction between mutated SMAD4 and SMAD3 and reactivated the cell growth inhibitory function of the SMAD4/SMAD3 complex. Collectively, these methods offer flexible strategies to target multiple tumor suppressor mutations.

Synthetic Lethal Targets

Experimental approaches derived from yeast genetics (Hartwell et al., 1997) have led to screening that identifies proteins whose activity is required for cancers carrying specific oncogenic mutations. Synthetic lethality makes it possible to target cancers that harbor mutations in non-drug proteins that could improve the therapeutic index. For example, the success of poly(ADP-ribose) polymerase (PARP) inhibition in the context of BRCA1 and BRCA2 deficiency has provided important proof of principle (Lord and Ashworth, 2017). PARP inhibition takes advantage of DNA repair defects caused by loss of BRCA1/2 and other homologous recombinant DNA repair mediators, leading to mitotic catastrophe. One mechanism of resistance to PARP inhibition is inversion of BRCA1 to induce a wild-type protein, confirming a direct relationship between the BRCA1 mutation and susceptibility to PARP inhibitors. Genome-wide genetic and small-molecule screens have recently identified several novel synthetic lethal combinations, including the discovery that WRN helicases are essential for survival of tumors with microsatellite instability (Chan et al., 2019) and BET, SRC and BCL2 family inhibitors in combination with PARP inhibitors (Lui et al., 2020).

Recent studies have identified new classes of synthetic lethal interactions. As predicted by Elledge and colleagues (Luo et al., 2009), some of these synthetic lethal genes are required to block cellular stress mechanisms induced by specific oncogenes. . For example, CSNK1E is required for the survival of Myc-amplified tumors (Toyoshima et al., 2012). Additional synthetic lethal opportunities are created when essential genes are located near tumor suppressors. CYCLOPS (Nijhawan et al., 2012) (Altered copy number confers responsibility for cancer due to partial loss of genes) was never homozygous for deletion and gene expression matched copy number. Suppression of the CYCLOPS gene causes cell death only in cells lacking the corresponding tumor suppressor gene due to copy number loss. For example, PRMT5 is required for the survival of tumors that lose MTAP, which is often lost because it is located near the commonly deleted tumor suppressor gene, CDKN2A (Mavrakis et al., 2016) (Kryukov et al., 2016) ). The CYCLOPS genes are currently the most common copy number-dependent genes (Tsherniak et al.) and likely represent a common pattern in composite cancer dependencies.

Finally, composite essentiality also occurs when deleting a paralog or family member makes one cell dependent on the other. For example, tumors containing deleted ENO1 require expression of ENO2 (Muller et al.,