Here we summarise a recent paper, published in Cell, that explored the landscape of therapeutic cancer targets beyond the list of recurrently mutated genes, highlighting novel opportunities for clinical translation.
Current approach
Most recently approved cancer drugs target specific oncoproteins encoded by somatically mutated genes. These drugs include proteins that are essential for the survival of specific cell lineages and proteins that inhibit immune responses. While large-scale efforts to sequence cancer genomes have facilitated the identification of recurrent mutations in cancer genes, deciphering this information has created a new challenge for cancer target discovery.
Work by the Cancer Target Discovery and Development Network and others has identified new categories of cancer targets beyond those inhibited by approved cancer drugs. The number and diversity of these targets to-date exceeds that of oncogenes found. This expanded repertoire of targets can be classified as tumour cell autonomous (intrinsic) or microenvironment-mediated (extrinsic). These factors can affect cancer cell plasticity and their persistence during therapy. Below we summarise the growing repertoire of intrinsic and extrinsic classes of targets as well as the therapeutic opportunities.
Tumour intrinsic targets
- Oncogene addiction: Oncogenic signalling in solid tumours is genetically complex. Copy number changes are among the most prevalent somatic mutational events in human cancers. In addition, dysregulated signalling represents an important conserved oncogenic mechanism. So far, oncogene amplification has proven challenging to target. Epigenetic regulators are also recurrently mutated in cancers and while they are also challenging to target as a class, they are becoming increasingly tractable e.g., DNMT inhibitors.
- Tumour suppressor rescue: Loss of tumour suppressor genes is common in cancers. There are several approaches to target these events in development. For example, a promising approach involves targeting mutant TP53 with drugs that stabilise its 3D-structure and restore its normal function.
- Synthetic lethal targets: Synthetic lethality allows targeting of cancers that harbour mutations in undruggable proteins with potential to improve therapeutic index. The most well-known success story is that of PARP inhibition in the setting of BRCA1/2 deficiency. Recent studies have also defined new classes of synthetic lethal interactions.
- DNA damage response (DDR): Deleterious events in genes that are involved in DDR are frequent across multiple tumour types. Understanding DDR is important to improve cancer outcomes. For example, defects in DDR can cause genomic instability which promotes oncogenesis. It can also sensitise cells to specific therapeutics. Identifying downstream effects caused by DDR remains another promising approach.
Emerging cancer targets
- Protein-protein interactions: Oncogenic missense mutations can alter protein-protein interactions and drive cancer progression. Identifying and characterising the key nodes and hubs in these protein-protein interaction networks may reveal unique opportunities for therapeutic intervention.
- Metabolic vulnerabilities: In order to rapidly proliferate, cancer cells require extensive cellular catabolic and anabolic metabolism to meet their energy and structural needs. Certain metabolic pathways are critical for the progression of selected cancers and can be exploited therapeutically.
- Cell states: Cell states represent high-dimensional vectors of variables that uniquely determine a cell’s phenotype. For example, a tumour may compromise multiple subcellular populations with different drug sensitivity, metabolism or stemness characteristics. Cell states can be stable (cells trapped for days), meta-stable (cells trapped for several hours), or transient (cells rapidly transitioning between states). Tumour progression and sensitivity to therapeutic agents largely depend on the presence of specific stable and meta-stable cell states.
- Master regulators: MR proteins represent the mechanistic regulators of transcriptional cell-state homeostasis. As a result, analysis of MR activity enables the identification of stable and meta-stable cancer-related cell states and cell-state transitions.
- Cell-state plasticity and resistance: Tumour-cell plasticity and adaptive responses to therapeutic stress play key roles in acquired drug resistance. A prime example are drug-tolerance cancer persister cells that are thought to arise from stochastic processes. These cells can present specific vulnerabilities.
Tumour microenvironment targets
Within the tumour microenvironment (TME), diverse non-neoplastic cell types and extracellular matrix (ECM) proteins interact to regulate the biology of cancer cells. Delving into these dynamic molecular exchanges has led to the development of therapeutic strategies that directly target aspects of the TME that are essential for tumour function. For example, anti-angiogenic treatments that target vascular endothelial growth factor (VEGF) and thus inhibit the tumour’s recruitment of new blood vessels. The TME spans immune cells, fibroblasts, ECM and neuronal elements – creating a multitude of potential therapeutic targets.
- Adaptive and innate immune cells: Recent TME-targeting strategies have focused on immune cells, spanning both adaptive and innate immunity. This includes macrophages, natural killer cells and dendritic cells. Modulation of immune function represents a high priority for cancer target identification and drug development. Strategies can exploit the immunogenicity of tumours and spur the host immune response. Advances in immunotherapy have transformed the cancer treatment landscape.
- Cancer-associated fibroblasts: Fibroblasts are abundant in normal and malignant tissues. Genetically, wild-type cancer-associated fibroblasts (CAFs) are intrinsically less able to acquire resistance to targeted agents compared to genomically unstable cancer cells. The CAF cell state changes during malignant progression and shares similarities to unstable cancer types, associated with therapy-resistant persister cancer cells.
Summary
Identifying robust therapeutic targets across cancer types is a high priority. While targeting somatically altered oncoproteins has been successful, many cancers fail to express oncogenes and resistance to single agent therapies rapidly develops. As a result, developing new therapies targeting the emerging classes of cancer targets described in this paper may target more patients but also provide complementary agents in combination regiments. The team note that the diversity of new types of cancer targets provides hope that all patients will benefit in the future from precision-medicine-guided therapies.
Image credit: By vitanovski – canva.com
