Targeting Mutations in Cancer

Introduction

Over the past few decades, improvements in the traditional cytotoxic chemotherapy, radiation, and surgical methods for treating cancer have decreased the mortality rates associated with the disease. However, significant obstacles still exist that frequently result in tumor recurrence and death. These difficulties have prompted research into cancer medicines that target specific mutations. Targeted treatments work on aberrant proteins encoded by altered genes as opposed to traditional chemotherapy, which employs cytotoxic chemicals to destroy rapidly proliferating malignant and healthy cells. Malignant and non-malignant cells frequently respond differently to targeted treatments because normal cells lack the tumorigenic mutations that are used for medication targeting. Since off-target toxicities are a feature of conventional chemotherapy, targeted therapy results in rapid and dramatic tumor shrinkage while restricting their potential. As a result, the creation of molecularly targeted drugs and the detection of tumor-specific actionable mutations have replaced cytotoxic medicines as the primary methods of drug discovery for cancer.

What Are the FDA-Approved Molecules With Mutation-Specific Indications?

• Sotorasib: First-in-class molecules for novel targets.

• Asciminib: This is used as a first-line treatment for a specific kind of chronic myeloid leukemia (CML, a type of cancer of the white blood cells) and in persons who have no longer benefitted from previous leukemia treatments.

• Amivantamab: A medication used to treat individuals with non-small cell lung cancer that has progressed to other regions of the body or that has specific mutations (changes) in the EGFR gene. It is given to people whose cancer has worsened as a result of platinum treatment.

• Infigratinib: Infigratinib is used to treat individuals who have previously had treatment for a specific kind of cholangiocarcinoma (bile duct cancer) that has spread to neighboring tissues or other regions of the body and cannot be removed surgically. Infigratinib belongs to a family of drugs known as kinase inhibitors.

• Tepotinib: Tepotinib is used to treat individuals with a certain kind of non-small cell lung cancer (NSCLC) that has progressed to other regions of the body. Tepotinib belongs to a family of drugs known as kinase inhibitors. It works by preventing an aberrant protein from signaling cancer cells to proliferate.

• Umbralisib: Umbralisib is used to treat individuals with marginal zone lymphoma (MZL, a slow-growing malignancy that starts in white blood cells that ordinarily fight infection) whose disease has returned or has not responded to a certain type of therapy.

What Are the Genetic Indications for Targeted Therapy in Cancer?

A variety of genes encoding kinases, tumor suppressors, and chromatin modifiers, as well as the downstream signaling effectors, are subject to targetable genetic abnormalities. These frequent genetic abnormalities that can be corrected with FDA-approved targeted treatments are listed below. The examples that follow showcase exemplary instances of genetic abnormalities and the related targeted therapies to show the advantages that targeted therapy may offer as well as the difficulties that must be faced when developing innovative medicines.

• Non-small Cell Lung Cancer: It occurs due to mutation and fusion of the ALK gene. Drugs like Alectinib, Brigatinib, etc., are used for the treatment of the same.

• Breast Cancer: This occurs due to the mutation of the ATM gene. Olaparib is used for its cure.

• Chronic/Acute Lymphocytic Leukemia: Because of the fusion of the BRE-ABL gene, chronic and acute lymphocytic leukemia takes place. Drugs like Bosutinib, Dasatinib, etc., are used for the treatment of it.

• Melanoma/Hairy Cell Leukemia/Thyroid Cancer: Occurs due to mutation of BRAF gene, uses drugs like Dabrafenib, Encorafenib, etc.

• Breast/Ovarian/Prostate: Mutation of the BRCA1/2 leads to them; Olaparib, Niraparib, Rucaparib, etc., are the set of drugs used to treat them.

• Giant Cell Tumor: CSF1R gene mutation causes giant cell tumors. Drugs like Peridartinib, etc., are used for the treatment of the same.

What Are the Targeting Modalities for Targeted Therapies in Cancer?

Using the HER1/HER2 RTK as an example, a common mode of drug availability is demonstrated to be associated with clinically approved molecules. Targeted therapies approved by the FDA include small molecule inhibitors and mAbs. Small molecule inhibitors are typically classified based on the mechanism by which they bind to their targets (inset). Small-molecule inhibitors in cancer can directly inhibit mutant protein products, inhibit hyperactivity/excess protein products together with WT proteins, or inhibit signal effectors downstream of mutant proteins. In addition to inhibitors, mAbs have been approved with or without the addition of drug conjugates that deliver cytotoxic payloads to target cells in addition to activating Antibody-dependent cellular cytotoxicity (ADCC).

What Is the Role of Tyrosine Kinases?

The number of possible targets has increased due to advances in sequencing, and the same targets are now more likely to be druggable thanks to advancements in chemical strategies. Tyrosine kinases and serine/threonine kinases are the two major categories of kinases. Tyrosine kinases work largely as growth factor receptors or in direct contact with growth factor receptors, whereas serine/threonine kinases react to a variety of physiological signals, including signaling downstream of tyrosine kinases. The ATP-binding pocket of the kinase can be occupied by kinase inhibitors in either an active (type I) or inactive (type II) conformation, as well as by allosteric inhibition of kinase activity (types III and IV). These include allosteric inhibition of kinase activity (types III and IV) through binding to other regions of the kinase, competition for ATP in the ATP-binding pocket of the kinase in either active (type I) or inactive (type II) conformation, and/or other mechanisms. In addition to pharmacological inhibitors, monoclonal antibodies (mAbs) that target the extracellular domains of tyrosine kinases have become a viable treatment strategy.

What Are the Mechanisms of Resistance to Targeted Therapies Against Kinases in Cancer?

Mutations in the kinase domain that limit drug binding to the target are the most common resistance mechanisms to kinase inhibitors. Alterations in drug transport or metabolism and mutations in downstream pathway effectors or alternative signaling pathway effectors are two additional routes of resistance to kinase inhibition. The most frequent forms of resistance with mAbs that target kinases are loss/downregulation/truncation of the targeted antigen. Phenotypic change, tumor heterogeneity, immunological dysregulation, and microenvironmental upregulation of ligands/growth factors are a few more typical resistance mechanisms that both small-molecule inhibitors and mAbs are susceptible to.

Conclusion

Over the past 20 years, mutation-specific targeted medicines have achieved great success and continue to be an attractive field of study. The number of cancer-related mutant genes that are thought to be druggable will probably rise during the coming ten years. An illustration of how innovative chemistry may be used to target a mutation that was formerly deemed "undruggable" is the creation of KRAS G12C inhibitors. Though there is currently no FDA-approved treatment for TP53 mutations, advances in targeted therapeutics are another area where innovative approaches may be used. For a variety of additional targets, new tactics and chemical methods are being researched. For instance, proteolysis-targeting chimeras (PROTACs) enable protein targeting by coupling the protein's ligand to an E3 ubiquitin ligase, leading to the target protein's breakdown by the proteasome. The varieties of proteins that may be targeted are considerably increased by this method since, unlike with conventional small-molecule inhibitors, no specific catalytic or other crucial location has to be blocked. Cancer vaccines and other mutation-specific targeted therapeutic approaches are also in the early stages of clinical testing.