Synthetic lethality

The first example of a molecular targeted therapeutic agent, which exploited a synthetic lethal approach, arose by means of an inactivated tumor suppressor gene (BRCA1 and 2), a treatment which received FDA approval in 2016 (PARP inhibitor).

[1] Theodore Dobzhansky coined the term "synthetic lethality" in 1946 to describe the same type of genetic interaction in wildtype populations of Drosophila.

[5] Synthetic lethality is a consequence of the tendency of organisms to maintain buffering schemes (i.e. backup plans) which engender phenotypic stability notwithstanding underlying genetic variations, environmental changes or other random events, such as mutations.

This genetic robustness is the result of parallel redundant pathways and "capacitor" proteins that camouflage the effects of mutations so that important cellular processes do not depend on any individual component.

[7] High-throughput synthetic lethal screens may help illuminate questions about how cellular processes work without previous knowledge of gene function or interaction.

Budding yeast has many experimental advantages in screens, including a small genome, fast doubling time, both haploid and diploid states, and ease of genetic manipulation.

A human Phase II clinical trial, with 41 patients, evaluated one synthetic lethal approach for tumors with or without MMR defects.

[15] A 2006 retrospective study, with long clinical follow-up, was made of colon cancer patients treated with the topoisomerase inhibitor irinotecan.

ARID1A, a chromatin modifier, is required for non-homologous end joining, a major pathway that repairs double-strand breaks in DNA,[22] and also has transcription regulatory roles.

For example, more than 20% of patients treated with an inhibitor of PD-1 encounter fatigue, rash, pruritus, cough, diarrhea, decreased appetite, constipation or arthralgia.