This document discusses synthetic lethality and its potential application to cancer therapeutics. Synthetic lethality occurs when the combination of mutations in two genes causes cell death, while mutation in only one gene is viable. The document outlines the history of synthetic lethality research and describes approaches to identify synthetic lethal gene interactions. Examples are given of synthetic lethal targets for common cancer gene mutations like p53, PTEN, MYC, and BRCA. Validating synthetic lethal targets and translating these findings into new drug combinations and personalized cancer treatments are areas of ongoing research.

1. IN THE NAME OF GOD

2. Synthetic lethality and cancer
Supervised by: Dr.Dastgheib
Presented by: Marjan Nouri Gorji

3. Outline
• Definition
• History
• Conditional synthetic lethality
• Types of SLI
• Approach for discovery
• SL targets validation
• SL database
• Translating SL into therapeutics
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Synthetic lethal interaction
Synthetic sick interaction

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History

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Conditional synthetic lethality
 Tumour cells are heterogeneous and are located in diverse environments
 Intrinsic: the genetic background and metabolic state of individual cells
 Extrinsic: the cellular microenvironment and exposure to therapeutic
agents

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 Conditional synthetic lethality could explain why some
genetic interactions are specific to a cell line.
 context-specific or private synthetic lethal interactions
 core or pan synthetic lethal interactions

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 Different types of synthetic lethal interactions are in
two broad categories:
1) interactions that are purely based on genetic mutations
2) interactions that involve existing cytotoxic agents that
are known to be effective in cancer patients

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 Loss-of-function mutations in tumour suppressors are
extremely common in human cancers.
 P53:
 mutated in 25 to 50 % ovarian, breast, colorectal, head and neck,
and lung cancers.
 difficult targe
 based on differential gene expression analyses, Wang and Simon
proposed a list of 98 candidate genes that, when suppressed, may
induce synthetic lethality in p53-deficient cancers.

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 PTEN
 Mendes-Pereira et al. demonstrated that cancers with PTEN
deficiency, which also cause HR defects, are sensitive to PARP
inhibitors.
 PARP inhibitors are currently in Phase II clinical trials for
treatment of PTEN-deficient cancers.

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 synthetic dosage lethality
 Example: constitutive activation of RAS signaling, particularly
KRAS, is known to be the oncogenic driver for approximately 20 %
of all human cancers.
 “undruggable” target due to the lack of suitable binding pockets for
small molecule inhibitors.
 hypersensitive to PLK1, APC/C, and proteasome inhibition

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 Hyperactivation of members of the MYC protein family
 C-MYC is amplified in about 10 % of LAC
 C-MYC, L-MYC or N-MYC amplification/overexpression occurs in
>20 % of SCLC.
 difficult to inhibit directly
 Inhibition of mTOR, Aurora A/B, SAE2, or CDK1 has been shown to
induce synthetic lethality in MYC-driven cancers.
 Synthetic lethal relationships:
 hyperactivated N-MYC and suppression of BRD4 in acute myeloid leukaemia
 hyperactivated N-MYC and suppression of CSNK1e in neuroblastoma

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 oncogenic mutations in KRAS and EGFR are mutually exclusive in
LAC.
 Unni et al. discovered that these two mutations are mutually
exclusive because activation of both genes in lung cells induces
synthetic lethality.
 From a clinical perspective, while it is challenging to increase
expression of a gene product, this study suggests that there may be
opportunities to activate combinations of pathways to induce
lethality.

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 Loss of heterozygosity or homozygous deletions results in complete
inactivation of a tumour suppressor;
 “passenger” or “neighboring” genes that are co-deleted
“unintentionally”
 These passenger genes may encode for housekeeping functions that
are essential to cell viability but are masked by the presence of
redundant genes encoded elsewhere to complement for the loss.
 Targeting homologues of these passengers forms the basis of
collateral lethality.

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 Example:
 ENO1
 homozygously deleted in glioblastoma (GBM) as a result of deletion in
the 1p36 tumour-suppressor locus.
 Enolase glycolysis
 GBM cells with deletion in 1p36 are highly sensitive to ENO2
inhibition due to collateral lethality.

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 Cisplatin:
 one of the most successful chemotherapeutics ever discovered for
cancer treatments.
 side-effects including nephrotoxicity, neurotoxicity, and ototoxicity
 Resistance to platinum based drugs is common
 combination products comprising cisplatin and a targeted treatment
 For instance, cancers with defects in DNA damage repair pathways,
such as BRCA mutations, are hypersensitive to DNA cross-linkers
including cisplatin, carboplatin, and mitomycin C.

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 combining two or more drugs with known single agent activity, different
mechanisms of action and non overlapping toxicities.
 maximized potential therapeutic benefits
 reducing the potential for development of resistance
 numerous successes; significant failures
 It is now apparent that some drug combinations work synergistically
through synthetic Lethality.
 cisplatin + gemcitabine; ovarian and NSCLC
 irinotecan + cisplatin; metastatic small-cell lung cancer

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Synthetic lethal candidates for cancer therapeutics are
available from three sources:

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Strategy for large-scale synthetic lethality screens
for a gene of interest in human cells

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synthetic lethal targets validation

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Synthetic lethality databases

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Translating synthetic lethality into therapeutics

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 In theory, there are three benefits to using a synthetic lethality-
based therapeutic strategy:
 First, it easy to identify patient responders.
 Second, large therapeutic window, limited adverse effects, lower
drug doses should be efficacious.
 Third, the strategy can be applied to any type of cancer mutation.

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 References:
1. O'Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet.
2017;18(10):613-23.
2. Leung AW, de Silva T, Bally MB, Lockwood WW. Synthetic lethality in lung
cancer and translation to clinical therapies. Molecular cancer. 2016;15(1):61.
3. George A, Kaye S, Banerjee S. Delivering widespread BRCA testing and PARP
inhibition to patients with ovarian cancer. Nat Rev Clin Oncol. 2017;14(5):284-96.

36. Thanks for your attention