Adoptive T cell transfer, Allosteric site, Clonal expansion, CRISPR-Cas9, DNA, DNA sequencing, EGFR, ‘Gain-of-function’ mutation, Genome, Genomic Instability, GTPase, GDP, GTP, Kinase, ‘Loss-of-function’ mutation, MAPK signaling pathway, Mutation, Oncogene/Proto-oncogene, Personalized Cancer Medicine, PI3K pathway, RAS, TP53 gene, Tumor suppressor gene
Cancer: a disease of the genome
Almost every cell in the human body contains the complete set of genetic information needed for an organism to function. This genetic information is stored in over three billion DNA molecules that are tightly packed into forty-six different continuous thread-like molecules known as chromosomes. Collectively, the DNA that constitutes all forty-six chromosomes is known as the genome. Occasionally, some errors known as mutations can arise within the genome when the cell is making a copy of its DNA during the process of cell division. Some of these mutations can cause certain cells to acquire the ability to grow and divide in an uncontrolled manner, leading to the formation of cancerous cells. These cells can acquire even more genomic mutations that allow them to subsequently invade surrounding tissue and spread to distant tissues in other parts of the body in a process called metastasis (3). For this reason, cancer can be described as a disease of the genome. It is the mutations within the DNA sequence that give rise to the development of cancer.
Cancer is a leading cause of death worldwide and consumes a significant proportion of the time and resources of healthcare systems. In the UK, one in two people are diagnosed with cancer over the course of their lifetime (2). A cancer diagnosis also has a devastating impact on both patients and their loved ones (3). Therefore, the continued advancement of scientific knowledge and development of novel therapeutic interventions is a requirement to improve clinical patient outcomes and facilitate greater benefits for everyone.
In the last two decades, unprecedented advances have been made in DNA sequencing. DNA sequencing is a method used to determine the sequence of nitrogenous bases, called nucleotides (Figure 1), that make up an individual’s DNA. Due to the advances made, DNA samples can be sequenced more quickly and cost-effectively. For example, in January this year, a new DNA sequencing technique developed by Stanford scientists was used to sequence the whole genome of a patient to diagnose them in under ten hours. This is an impressive feat when compared to standard genome sequencing-based diagnosis which can take several weeks (4). These super-fast sequencing techniques have made it possible for cancer research scientists to easily identify and compare the differences between the genomes of cancer cells with those of normal cells. This new capability has helped to usher in the era of personalized cancer therapeutics which allows doctors to select specific therapies based on the genetic makeup of an individual’s tumor (Figure 2).
This article will briefly outline the journey to the personalization of cancer treatment, focusing on the recently approved landmark drug, Sotorasib, as an example. This article aims to illustrate the huge potential that exists for further research and development of personalized therapeutics based on the ever-increasing knowledge of the vulnerabilities of cancer cells. More importantly, it is hoped that this article may be a source of information for patients and/or their loved ones.
Chemotherapy: a gold-standard treatment
Since the time of Sidney Farber’s discovery in the late 1940s that childhood leukemias can be treated with folic acid antagonists (drugs that block cells from using folic acid to make DNA) (5), the ‘War on Cancer’ was launched, with the aim of discovering a magic bullet. It is now known that the prospect of discovering a single magic bullet to treat cancer is unfortunately a fallacy. Far from being a single disease, cancer is in fact a highly heterogenous group of hundreds of diseases characterized by differences in the cell of origin and the types of genetic aberrations that are present within an individual’s tumor. Different cancers vary widely in their responses to conventional therapies and consequently, no single drug will have the capability to cure all cancers (2).
Despite the improvements that have been made to chemotherapeutics over the years, patients are still subject to grueling and lengthy treatment regimens and often suffer debilitating side effects. Furthermore, as a result of the ability of cancer cells to develop drug resistance, chemotherapies are often ineffective in the long term, with cancers often recurring at some point after the treatment has been completed (6). Most chemotherapeutics drugs are designed to target rapidly dividing cells and while this does kill cancer cells, many normal cells that are rapidly dividing are also killed. This causes a range of side effects such as hair loss, susceptibility to infection, and anemia (7). By using data gained from DNA sequencing and comparing the genomes of cancer cells with that of normal cells, researchers have developed therapeutics that can kill cancer cells and avoid damage to normal cells by targeting a cancer-specific mutation. This significant advance has brought in a promising new era of personalized cancer medicine. This more personalized approach to cancer treatment aims to design treatments that are more specific and effective, and that cause less side-effects.
Advances in DNA sequencing technologies & targeted cancer therapeutics
Since the completion of the Human Genome Project in 2003, sequencing technologies have improved exponentially in terms of the volume of information that they can generate and the speed and cost at which they can do so. This has provided cancer research scientists with a wealth of information regarding what differentiates cancer cells from normal cells at the molecular level. This sequencing data has revealed just how distinct the genetic makeup of each individual’s disease actually is, both between inter-tumor heterogeneity (tumor by tumor variations) and even intra-tumor heterogeneity (where cells within the same tumor specimen possess distinct biological features). The differences are so distinct that most cancers have been split into different molecular subtypes based on defined genetic abnormalities. An example of this is the specific molecular classification of breast cancer. Many breast cancer cells have proteins on their cell surface known as receptors that can bind to the hormones estrogen and progesterone. Another common receptor that can be produced in large quantities on the cell surface of breast cancer cells is the HER2 protein. Breast cancer can be molecularly subtyped based on the activity of the genes producing these different protein receptors and also another protein called Ki67 which helps control how fast cancer cells grow in breast cancer cells. The four main molecular subtypes are luminal A, luminal B, HER2-enriched and triple-negative breast cancers. This is where targeted cancer therapeutics comes in. Doctors can identify and categorize patients’ tumor into characteristically different groups. In this way, doctors can then accordingly administer drugs tailored to target the specific molecular differences between cancer cells and normal cells in patients (Figure 2).
Oncogenes and Tumor Suppressor Genes (TSGs)
The discovery of TSGs and oncogenes has significantly enhanced our understanding of cancer as a disease of the genome. Under normal circumstances, TSGs function to prevent a cell from behaving abnormally and becoming cancerous. A well-known example of such a gene is TP53, the so-called ‘guardian of the genome’. The TP53 gene earned this label due to the critical role that it plays in detecting the presence of DNA damage within a cell and in initiating responses such as DNA repair or cell death in cases of cellular insults. These processes can eliminate cancer cells by preventing their replication and the subsequent inheritance of these mutations by daughter cells. However, in many cancers, the protein p53, which is encoded by the TP53 gene, is unable to function normally as a result of acquiring a ‘loss-of-function’ mutation. This type of mutation decreases or nullifies the function of p53, making the cell more vulnerable to the accumulation of DNA damage. The more mutations that a cell accumulates, the greater the likelihood of these mutations may arise within critical genes. This increases the risk of developing cancer (Figure 3).
When functioning normally, an oncogene, is termed a proto-oncogene. Proto-oncogenes are genes that have the potential to contribute to the malignant transformation of a cell if they become dysregulated. For example, if genes that encode proteins involved in the growth and division of cells acquire a ‘gain-of-function’ mutation, they become overactive or unable to be ‘switched off’. This can lead to cells growing and dividing in an uncontrolled manner which would contribute to the development of a cancer (Figure 3).
RAS: a proto-oncogene
A well-known example of a proto-oncogene is the RAS gene. The three variants of the RAS protein (isoforms) are HRAS, NRAS, and KRAS. These proteins are encoded by different RAS genes, but have similar functions. The RAS proteins play an important role in controlling a range of essential cellular processes including cell proliferation, differentiation, and survival. Cell differentiation is a term used to describe the process by which an immature, young cell becomes specialized for a particular function. For example, an unspecialized blood stem cell can differentiate into a specialized white blood cell.
Normally, cells are programmed to self-destruct when they become faulty. This is to prevent the formation of cancers and other diseases. However, faulty cells may be able to survive and divide into a tumor if cellular processes that are involved in survival and proliferation are not functioning normally. The inability of cells to differentiate properly can give them certain survival advantages and a lack of regulation of any other cellular processes controlled by RAS can result in the development of cancer.
RAS proteins are a type of enzyme called ‘GTPases’ that function as binary molecular switches, alternating between an active and inactive form. Often located close to the cell membrane, RAS proteins become active when the cell receives external stimuli such as growth and /or proliferation signals through protein receptors like EGFR. Mechanistically, this occurs when a small molecule called GTP binds to the RAS protein, engendering a change in the shape of RAS which facilitates its activation (9) (Figure 4). Subsequently, the activated RAS proteins trigger a chain of specific reactions such as the MAPK and PI3K pathways, by switching on other relevant proteins to amplify and relay signals inside the cell in a process called signal transduction. Ultimately, the activation of these pathways switches on genes that are involved in cell growth, differentiation, and survival (Figure 4). Once the RAS proteins have triggered an internal response, a phosphate group is removed from GTP, resulting in a molecule called GDP (Figure 4). This causes the RAS protein to adopt a relaxed form, thereby causing its inactivation and its inability to trigger signal transduction (9). This process of cycling RAS proteins between an active and inactive state is tightly regulated to ensure that RAS-mediated signal transduction only occurs in the correct circumstances.
KRAS is the most frequently mutated proto-oncogene in human cancers (10). Disregulated RAS-mediated signaling usually occurs as a result of mutation-induced activation in the RAS proteins, which puts them into their GTP-bound active state. Abnormal RAS-mediated signaling can also occur due to mutations in proteins that relay signals to the RAS proteins, that is, in proteins that are activated earlier in the signaling cascade (upstream proteins). Similarly, mutations in proteins that are activated later by RAS in the signaling cascade (downstream proteins) can also lead to dysfunctional RAS-mediated signaling. This leads to aberrant, oncogenic signaling and tumorigenesis (development of a tumor) (9). The Cancer Genome Atlas found alterations in the RAS-mediated signaling pathway in 46% of all human tumor samples that were screened, rendering it the most frequently altered oncogenic pathway (11). Specifically, KRAS was the most frequently altered gene in pancreatic, colorectal and lung cancer samples (11). The KRAS gene is now known as a cancer driver gene since mutations in the KRAS gene are known to be key in facilitating the formation of these three cancers (12). For example, the mutated gene can enhance the ability of cancer cells to grow and divide even in the absence of growth signals, thereby driving tumorigenesis (13). Consequently, great efforts have been made towards developing inhibitors of mutant KRAS. Despite various drugs targeting upstream and downstream components of the RAS-mediated signaling pathway reaching clinical approval over the past few decades, direct inhibition of oncogenic RAS proteins has remained elusive. Owing to a lack of suitable binding sites on the surface of RAS for which to design inhibitors, the RAS proteins were deemed ‘undruggable’ for decades, until recently (12).
Targeting oncogenic RAS
Indirect targeting of RAS signaling
The activation of EGFR leads to the activation of RAS by promoting the exchange of GDP for GTP. Therefore, it follows that targeting EGFR should be a feasible strategy by which to indirectly inhibit RAS-mediated signaling pathways. Successful efforts to target EGFR have resulted in the approval and clinical use of EGFR inhibitors in various cancer types (14). However, if the mutations that lead to aberrant RAS-mediated signaling occur downstream of the EGFR, then inhibition at the receptor level is redundant and will not inhibit the oncogenic signaling.
Targeting signaling transduction pathways activated by RAS, such as the MAPK pathway, has also been found to be an effective strategy for inhibiting the pro-oncogenic signals that are transmitted by mutant RAS proteins in cancers. RAF, MEK, and ERK are enzymes termed ‘kinases’ that form the MAPK pathway. When these enzymes are activated abnormally, it culminates in the aberrant activation of cellular processes that contribute to tumorigenesis (Figure 3) (15). Inhibitors against all three aforementioned kinases are in clinical use in specific cancer types (9, 12). The PI3K pathway is another important RAS-mediated signaling pathway. Inhibitors against some of the key components of this pathway such as p110, AKT and mTOR, are also in clinical use (9).
In order for RAS to be activated and to function, it must be located at the cell-surface membrane where accessory proteins aid in the processing of RAS and the exchange of GDP for GTP. These offer alternative routes by which to indirectly target RAS, preventing its translocation to the cell surface (12).
Sotorasib and direct targeting of mutant KRAS
Despite the challenges encountered in attempting to target RAS directly, efforts to identify a direct inhibitor of the oncogenic RAS protein continue. Success in identifying such an inhibitor would add an important weapon to the arsenal of RAS-targeting therapeutics and provide another option for the large proportion of individuals with RAS-driven tumors. It is worth noting that the RAS protein is essential for the function of normal, non-cancerous cells. Therefore, when developing a direct RAS inhibitor, it is necessary to selectively target mutant versions of RAS only, to avoid disrupting the function of the normal RAS enzyme. This has added a further layer of complexity to RAS-inhibitor drug discovery.
Shokat et al made the crucial discovery of an allosteric binding pocket on the surface of KRAS-G12C, which is a common, mutant version of KRAS (16). The RAS allosteric binding pocket is a location within the folded protein where it is possible for a molecule other than GDP or GTP to bind. When a complementary molecule binds to this allosteric site, it changes the shape of RAS and influences its ability to be active. KRAS mutations occur in one in four patients with non-small cell lung cancer (NSCLC), with 11-16% of those being KRAS-G12C mutations (17). The G and C in G12C refer to a specific amino acid change that has occurred within the KRAS protein from the amino acid glycine (G), to the amino acid cysteine, C, at position 12 in the sequence of amino acids that make up the protein. Shokat and colleagues designed an inhibitor that could irreversibly bind to KRAS using the mutant cysteine amino acid. This means that the inhibitor is selective for this oncogenic version of the enzyme and therefore, does not affect normal cells. As a result of this inhibitor binding, KRAS-G12C favors GDP over GTP and is therefore locked in a GDP-bound, inactive state. This leads to an accumulation of inactive KRAS, which largely diminishes tumorigenic signaling by KRAS (Figure 5) (16). After further developments of the initial inhibitor by a company called Amgen (10), an optimized compound called AMG 510 (Lumykras) entered into clinical trials. This culminated in its Food and Drug Administration (FDA) fast-track approval in May 2021 for refractory (treatment-resistant) metastatic NSCLC patients with mutant KRAS-G12C who have already previously received at least one other systemic cancer therapy (10, 18). Alongside the FDA approval for the targeted inhibitor itself, two tests that can identify the presence of the KRAS-G12C mutant in a patient’s tumor were also approved. These tests can aid in identifying patients who are likely to benefit from the targeted therapy (19). The Medicines and Healthcare products Regulatory Agency (MHRA) approved Sotorasib for National Health Service (NHS) lung cancer patients who have already been treated with platinum-based chemotherapy and/or immunotherapy in September 2021.
The problem of resistance
Despite the impressive advancements that have been made in developing targeted cancer therapeutics over the past twenty years, the emergence of treatment resistance remains a significant challenge. Douglas Hanahan and Robert Weinberg published a renowned scientific paper detailing the ‘Hallmarks of Cancer’ to aid our understanding of this highly complex disease. The paper highlighted that cancer cells’ ‘genomic instability’ underlies the six core hallmarks of cancer (20). In other words, an increased rate of cell division, and therefore DNA replication, as well as defects in DNA repair systems lead to the accumulation of DNA mutations. This can directly or indirectly enhance the ability of cancer cells to survive and proliferate. This genomic instability and the corresponding diversity of a cancer genome give cancer cells the ability to develop resistance to currently available treatments.
Certain mutations acquired by a small proportion of cancer cells can enhance the ability of these cells to survive exposure to anticancer drugs and to outcompete more vulnerable tumor cells. This is called a selective advantage. A tumor can initially appear to shrink in size following the initial administration of a targeted therapeutic, but then recur shortly thereafter. This is due to rapid division and proliferation of those cancer cells that survived the treatment due to their selective advantage (Figure 6). This advantage could be due to the upregulation of a compensatory pathway to overcome the therapeutic inhibition of a particular pathway. In the case of Sotorasib, which works by binding to the GDP-bound inactive state of KRAS, cancer cells may develop a resistance mechanism by acquiring a mutant version of the protein that is locked in the GTP-bound active state. This prevents the drug from binding and inhibiting KRAS, and as a result, tumor cells continue to divide uncontrollably. Another possible scenario is that proteins which are downstream of RAS in a signaling pathway could acquire activating mutations. In this case, the mutated downstream proteins could switch on RAS-mediated signaling pathways independent of RAS activation. This also renders Sotorasib ineffective.
Using combinatorial treatment approaches is one method of combating the emergence of resistance. In this approach, more than one pathway or more than one component of a particular pathway are targeted simultaneously. In the case of Sotorasib, combining this drug with a MEK inhibitor (MEK is a protein kinase downstream of RAS in the MAPK pathway) has been shown to be effective in the early phases of drug development research (10). However, when using a combination of drugs, the issue of toxicity arises. For the doctor, it becomes a balancing act of attempting to reduce the chance of resistance developing, while minimizing toxicity and side effects for the patient. A further possible approach is the use of immunotherapy in combination with Sotorasib. Immunotherapy harnesses the immune system by directing it to destroy and eliminate cancer cells specifically. One immunotherapy approach that has seen success in the clinic is immune checkpoint blockade. This technique works by ‘releasing the brakes’ on the immune system, thereby enabling it to recognize and kill cancer cells. Combining Sotorasib with immune checkpoint blockade has also shown promise in the early phases of drug testing (10). A clinical trial (NCT03600883) is currently being conducted to evaluate the effectiveness of combining Sotorasib with immune checkpoint blockade/MAPK pathway inhibitors (21).
Future of RAS-targeting approaches
Despite the landmark approval of Sotorasib in 2021, it is worth noting that while KRAS-G12C is a common mutant, it still only accounts for a subset of the mutations harbored by KRAS in human cancer. Work to develop other KRAS inhibitors that are specific for other mutant versions is currently underway. The development of ‘pan-RAS’ inhibitors that target all the mutant versions of RAS contained in a tumor is also ongoing. However, these inhibitors may be toxic as they can also target normal RAS proteins in healthy cells (12).
Another approach to target KRAS mutations involves the gene editing system known as ‘CRISPR-Cas9’, which acts as molecular scissors to remove, add, or alter specific sections of DNA. Using this genome editing tool, Gao et al. were able to induce tumor regression by selectively targeting and depleting the KRAS-G12S mutation in mouse models of cancer (22). The authors propose investigating the possibility of selectively targeting KRAS mutations and other oncogenic mutations using the CRISPR-Cas9 system.
The potential of harnessing the immune system to target RAS also holds promise. T-cells are white blood cells that are a key component of our immune system. They can target and kill specific cell types, whether these are cells infected with an invading microorganism such as a virus, or cancerous cells. However, tumor cells also possess the ability to evade and even suppress the immune system. Therefore, strategies to overcome the cancer’s suppression of the immune system and direct it towards killing tumor cells are promising and exciting areas of research. One immunotherapeutic strategy being explored is adoptive T-cell transfer. This technique involves isolating naturally-occurring T-cells from the patient. These cells can recognize the patient´s specific RAS mutation. They can be isolated and expanded to millions in the lab. The cells are then infused back into the patient (23, 24). While this strategy has shown promise in clinical trials, further development of this technique is needed to improve response rates, prevent disease recurrence and T-cell manufacturing capabilities.
This is an exciting time, not only for the field of RAS-targeted therapies, but for cancer care in general. With personalized cancer medicine increasingly forming a part of routine care, there is hope for improving both patient outcomes by targeting the specific vulnerabilities of a patient’s tumor, and bettering quality of life by reducing the debilitating side effects associated with traditional chemotherapies. The continuing advances in genomic sequencing capabilities, ‘big data’ computational analysis, artificial intelligence, and biotechnological advances are driving innovation and the development of more personalized cancer therapeutics for many different types of cancer. This personalization offers great hope for cancer patients who will have the chance to receive more effective treatments with less side-effects.
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