Synthetic lethality is a precision medicine strategy that’s long promised results. Finally, it’s showing signs of helping to beat cancers that were previously thought of as ‘undruggable’. The concept of synthetic lethality has been talked about for decades (it was first described in 1922). But it’s only since 2005 that synthetically lethal interactions have been translated into the clinic for cancer patients.[1][2][3][4].
Today, researchers and clinicians are more excited than ever about the potential for synthetic lethality as a new wave of genetically based cancer medicines undergoing development. These precision medicines could help to treat cancer in a way that largely leaves a patient’s healthy cells unharmed.[4]
A synthetic lethality-based treatment strategy has two major advantages: firstly, it can be utilised against the majority of cancer mutations and secondly it allows us to identify patients who are most likely to respond to treatment.
A precision approach
Synthetic lethality can be applied in drug discovery to develop medicines that target specific genetic mutations expressed only in cancer cells, and not present in normal cells.[4], Genetics play a heavy role in progression of the disease; therefore, patients who would benefit the most from a synthetic lethal therapy can be preselected based on their cancer genetic profile, increasing the likelihood of response and reducing toxicity.[4][5]
The concept of synthetic lethality applies to pairs of genes whose functional loss can be tolerated singly but not in combination.[4] Tumour suppressor genes, which control cell growth, are often deleted or mutated in cancer cells allowing them to sustain uncontrolled growth.[4] Because the function of these tumour suppressor genes are lost in cancer cells, they are not amenable to traditional direct interacting medicines.[4]
Since tumour suppressor genes cannot be directly targeted, we can leverage synthetic lethality by identifying and targeting the lethal gene partner; this leads to death of cancer cells whereas normal cells that retain function of the related tumour suppressor gene are spared this effect.[4] Identification of druggable synthetic lethal partners is currently the only way of targeting the functional loss of tumour suppressor genes in cancer.[4]
How synthetic lethality is advancing
The first synthetic lethal interaction found in cancer was between poly (ADP-ribose) polymerase (PARP) and the tumour suppressor genes BRCA (BReast CAncer gene) 1 and 2. Gene products of PARP and BRCA1/BRCA2 normally function to repair DNA damage.[4] During the development of certain cancers, genes such as BRCA1/BRCA2 are mutated and non-functional, which limits the repair of DNA in these cancer cells. PARP inhibitors selectively inflict high levels of damage to cancer cells, which cannot be repaired, while normal cells use the intact BRCA1/2 to remain healthy. This is a successful example of synthetic lethality, which is now being used to treat BRCA mutated cancers.[4]
Exploiting the synthetic lethal concept in the DNA damage repair pathway is currently of high interest to me. It now appears that a clinically significant fraction of cancers do have DNA repair defects.
How new research methods and technologies are changing the game
In order to discover new synthetic lethal gene pairs, we need to use new technologies that change our approach and enhance our ability to understand the research in the space. When you consider the exponential number of potential synthetic lethal gene pairs in the human genome, this requires technologies that interrogate vast amounts of data.[4]
For many years, data was obtained through genetic screening for loss-of-function mutations in yeast or by use of genetic tools in human/mammalian cells, however these technologies were limited by the reliance on conserved genes (those that have been unchanged throughout evolution and are present across species), or inaccuracies when experiments were scaled up.[4][6][7][8] Today CRISPR (clustered regularly interspaced short palindromic repeats)-based tools and libraries offer a path forward, where ‘hits’ (i.e. potential drug targets) can be generated, and the patient population expected to benefit from inhibiting each target is already known.[4]
Over the next five to ten years, I hope research leads us to identify novel synthetic lethal partners beyond PARP inhibition and BRCA mutation to help expand the patient population that can benefit from this science.
Building synthetic lethality from concept into reality at GSK
CRISPR-based tools have revolutionised the discovery of several synthetically lethal combinations that are currently in clinical trials. This progress demonstrates the potential of CRISPR technology to dramatically alter cancer target discovery and create a wave of new therapeutics over the next decade.[4][9]
At GSK, our industry-leading synthetic lethality research unit is working to advance our preclinical programme portfolio while further understanding the underlying mechanisms of synthetic lethality drug resistance. Our larger vision in R&D is to identify novel targets in drug-resistant patient populations, underpinning our goal to deliver potentially transformational medicines in oncology.
In June of 2020, GSK and IDEAYA Biosciences formed a strategic partnership to advance novel synthetic lethality assets, including as monotherapy and as combinations between GSK and IDEAYA programs. This partnership enables compelling potential combinations and the opportunity to build an industry leading pipeline that targets molecularly defined populations in several major solid tumours. The collaboration has the potential to bring the next generation of innovative precision medicine therapies to patients utilising the approach of synthetic lethality and could have meaningful impact for the clinical care of patients with lung, prostate, breast, colorectal and ovarian cancers.
References
[1] Bridges, C. The origin of variations in sexual and sex-limited characters. Am. Nat. 1922;56(642):51-63.
[2] Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-21.
[3] Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355(6330):1152-8.
[4] Huang A, Garraway LA, Ashworth A, et al. Synthetic lethality as an engine for cancer drug target discovery. Nat. Rev. Drug Discov. 2019;11:1-6.
[5] Behan FM, Iorio F, Picco G, et al. Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens. Nature. 2019;568(7753):511-6.
[6] Kaelin WG. Choosing anticancer drug targets in the postgenomic era. J Clin Invest. 1999;104(11):1503-6.
[7] Kaelin WG. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer. 2005;5(9):689-98.
[8] Hartwell LH, Szankasi P, Roberts CJ, et al. Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997;278(5340):1064-8.
[9] Jariyal H, Weinberg F, Achreja A, et al. Synthetic lethality: a step forward for personalized medicine in cancer. Drug Discov. Today. 2020;25(2):305-20.
