What is Targeted Therapy?

Targeted therapy is a cancer treatment modality that involves directing therapeutic compounds to specific genes, proteins and pathways associated with tumor progression and growth. Unlike cytotoxic chemotherapy methods, which affect both healthy and cancerous cells, targeted therapies aim to limit cytotoxicity to only the cancerous cells.¹

Targeted therapies form the backbone of precision medicine because they can be tailored to each patient's unique tumor biology. By interfering with the molecular drivers of tumor growth, survival and metastasis, these therapies can enhance patient survival rates, reduce side effects and improve long-term outcomes.¹

Several classes of drugs are used in targeted therapy, including:¹

• Monoclonal antibodies
• Small-molecule inhibitors
• Antibody-drug conjugates (ADCs)
• Immune-modulating agents

How Targeted Therapy Works?

Depending on the type of therapeutic compound used, a targeted therapy may exhibit one of many mechanisms that disrupt growth, survival, immune evasion and metastasis.

Blocking Growth Signals

Signal transduction pathways, which relay signals from external stimuli to the nucleus or organelles to determine cellular function or behavior, are often overactivated in cancers, manifesting as rapid and uncontrolled proliferation. This overactivation is often due to mutations in signaling proteins or receptors. Targeted therapies modulate constitutive activation of signaling pathways by inhibiting mutated or overexpressed receptors and receptor tyrosine kinases. Common targets include:²

• Epidermal growth factor receptor (EGFR)
• Human epidermal growth factor receptor 2 (HER2)
• BRAF
• Anaplastic lymphoma kinase (ALK)

Inhibiting the activity of these proteins regulates essential downstream signaling pathways, such as the MAPK or PI3K/AKT pathways, ultimately slowing tumor growth and inducing shrinkage.³

Stopping Blood Vessel Formation

Tumors form an abnormal and dense vasculature for a steady supply of oxygen and nutrients, which are essential for growth. Anti-angiogenic therapies prevent the formation of new blood vessels by:⁴

• Blocking VEGF (vascular endothelial growth factor), a key signal that triggers vessel formation
• Inhibiting VEGF receptors on endothelial cells to prevent vessel growth from being initiated
• Disrupting the structural development of newly formed vessels, making them unstable and nonfunctional

Disrupting the blood supply causes tumor cells to starve, limiting their growth and survival.⁴

Delivering Toxins to Cancer Cells

Some targeted therapies serve as delivery systems that carry potent cell-killing agents directly into cancer cells. The delivery vehicle is designed to recognize tumor-associated proteins, thereby achieving highly localized toxicity while sparing healthy cells. Examples include:

• Antibody-drug conjugates (ADCs), which link a monoclonal antibody to a toxic payload that is released inside the tumor cell⁵
• Radioimmunotherapy, where antibodies deliver radioactive isotopes to cancer cells6
• Ligand-targeted toxins, which bind to overexpressed receptors on cancer cells⁷

Helping the Immune System

Cancer cells often hijack the immune system, rendering immune cells ineffective in recognizing and attacking these cells. Specific targeted therapies restore and enhance the immune system's ability to recognize and destroy cancer cells. They work by:⁸

• Blocking immune checkpoint inhibitors like PD-1, PD-L1 or CTLA-4, which cancers use to hide from immune cells
• Activating co-stimulatory pathways that boost T-cell activity
• Targeting tumor-specific antigens to flag cancer cells for immune attack

These therapies help the immune system mount a stronger and more sustained anti-cancer response.⁸

Causing Self-Destruction

Although apoptosis (i.e., self-programmed death) is an intrinsic capability of a healthy system to eliminate damaged or abnormal cells, this mechanism is significantly downregulated in cancer cells. Some targeted drugs restore or trigger apoptosis by:⁹

• Inhibiting proteins like BCL-2, which cancer cells use to avoid cell death
• Activating death receptors or downstream caspases
• Disrupting mitochondrial pathways that regulate programmed cell death

Reactivating apoptosis can trigger a better-controlled self-destruction of cancer cells, slowing or stopping tumor growth.⁹

Types of Targeted Therapies

Targeted therapies come in several forms, each designed to act on specific molecular features of cancer cells.

Small-Molecule Drugs

Small-molecule drugs are compounds with low molecular weight that can enter cells seamlessly and act as inhibitors of proteins associated with tumorigenesis. They commonly target kinases (e.g., EGFR, BRAF, ALK, JAK), which are often mutated in cancer to drive uncontrolled growth. Subsequently, the aberrant activation of intracellular pathways such as PI3K/AKT or MAPK is interrupted. ¹⁰

Hormone Therapy

Some cancers, mainly breast, prostate and ovarian cancers, rely on hormones for growth. Hormone therapies slow or reverse hormone-driven growth by blocking hormone receptors on cancer cells, which prevents the binding of estrogen, progesterone or androgens. Thus, they interfere with the subsequent activation of hormone-driven signaling pathways. Other hormone therapies modulate or block the hormone-producing capabilities of the patient's body.¹¹

Angiogenesis Inhibitors

As tumors grow in size, an urgent need for a blood supply arises to maintain and escalate tumor development. Angiogenesis inhibitors prevent tumors from building new blood vessels, starving them of nutrients and oxygen. VEGF inhibitors or compounds that bind VEGF receptors are typical examples, as they disrupt endothelial cell function, preventing the formation and spread of newly formed vessels.¹²

Gene Expression Modulators

Many cancer types are characterized by the overactivation of oncogenes and the suppression of tumor suppressor genes, as well as the dysregulation of epigenetic modifications that are responsible for gene regulation. Gene expression modulators aim to restore healthy gene expression by silencing oncogenes and reactivating tumor suppressor genes. Other modulators, such as inhibitors of histone deacetylase (HDAC) and DNA methyltransferase, target epigenetic regulation.^13,14

Apoptosis Inducers

Apoptosis inducers restore or trigger programmed cell death in cancer cells that have downregulated their apoptotic pathways. Their functions include blocking anti-apoptotic proteins, activating death receptor pathways and mitochondrial-mediated apoptosis.⁹

Immunotherapy

Immunotherapy is a specialized form of targeted therapy that harnesses and enhances the immune system's ability to detect and eliminate cancer cells. Although immunotherapy itself is not a targeted therapy, certain types of immunotherapies overlap with the definition of targeted therapy. Monoclonal antibodies are ideal examples. By binding to tumor-associated antigens or receptors on various types of immune cells, they direct the immune system toward cancer cells.¹⁵ On the other hand, immune checkpoint inhibitors target and block checkpoint proteins, such as CTLA-4 or PD-1, which regulate immune activity in healthy individuals but prematurely block it in cancer, allowing cancer cells to evade attacks. They are often combined with other targeted therapies to achieve a synergistic anticancer effect.¹⁶

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How is targeted therapy different from chemotherapy?

Chemotherapy uses cytotoxic drugs that attack all rapidly dividing cells. Because these drugs cannot distinguish between tumor cells and healthy cells, they often act on those in hair follicles, the digestive tract or bone marrow. Therefore, they can cause broader side effects such as hair loss, nausea, fatigue and lowered immunity.¹

Targeted therapy, on the other hand, is designed to act on specific molecules or genetic abnormalities that are unique to cancer cells or overactive in tumors. Instead of damaging all fast-growing cells, these drugs focus on specific pathways. As a result, they cause fewer off-target effects and can be easily tailored to specific patient profiles.¹

What cancers can be treated with targeted drug therapy?

Targeted therapies are effective against many types of cancers, particularly those with identifiable molecular changes or genetic mutations. The choice of treatment depends on the tumor-specific biomarkers and pathways.

Lung Cancer

Lung cancer subtypes, especially non-small cell lung cancer (NSCLC), harbor mutations in EGFR, ALK, ROS1, KRAS and MEK. Tyrosine kinase inhibitors (e.g., Osimertinib for EGFR or Crizotinib for ALK/ROS1) are targeted therapies that block the signaling pathways driving uncontrolled cell proliferation. These drugs were shown to shrink tumors and reverse tumor progression in patients whose tumors are characterized by one or more of these mutations.¹⁷

Breast Cancer

HER2-positive breast cancer overexpresses the HER2 receptor, leading to aggressive tumor growth. HER2-targeted therapies such as trastuzumab, pertuzumab and T-DM1, bind to this receptor and block growth signals. HER2 can also be targeted to deliver cytotoxic agents directly to cancer cells. In addition, hormone therapies, such as tamoxifen, block estrogen-driven signaling in hormone receptor-positive breast cancers.^11,18

Colorectal Cancer

Targeted therapies have become especially effective in advanced-stage and metastatic colorectal cancers (CRC), although the genetic makeup of the tumor is essential for deciding the best treatment option. For instance, monoclonal antibodies, such as cetuximab and panitumumab, demonstrate efficacy in EGFR-overexpressing CRCs unless the tumor also harbors KRAS/NRAS mutations. Other monoclonal antibodies, such as bevacizumab, target VEGF to prevent angiogenesis and drive starvation. Finally, BRAF inhibitors are preferred for patients with CRC who carry the BRAF V600E mutation and can be used in conjunction with EGFR inhibitors.¹⁹

Leukemia & Lymphoma

The ideal targeting strategy depends on the subtype. Therapies targeting chronic myeloid leukemia (CML) aim to inhibit the BCR-ABL fusion protein, which promotes and accelerates cell proliferation and growth.²⁰ On the other hand, B-cell lymphomas are treated with monoclonal antibodies (e.g., rituximab) that trigger immune-mediated cell death.²¹

Melanoma

Mutations in the MAPK pathway are frequently observed in melanoma. BRAF inhibitors (e.g., vemurafenib and dabrafenib) and MEK inhibitors (trametinib, cobimetinib) block the MAPK signaling pathway, slowing tumor growth and improving survival rates.²²

Prostate Cancer

A significant portion of prostate cancers are hormone-driven. For these prostate cancer subtypes, androgen deprivation therapy (ADT) is frequently used to reduce testosterone levels or block androgen receptors.²³ Furthermore, some prostate cancers harbor mutations in DNA repair genes such as BRCA1/2 or ATM. Targeted therapies aim to block aberrant DNA repair in cancer cells, resulting in the accumulation of DNA damage and ultimately leading to cell death.²⁴ The PI3K/AKT/mTOR is another targetable pathway, especially in PTEN-deficient prostate cancers.²⁵

Ovarian & Other Gynecologic Cancers

Ovarian and other gynecologic cancers are also characterized by dysregulated DNA repair mechanisms, such as homologous recombination deficiency (HRD). Poly (ADP-ribose) polymerase (PARP) inhibitors can help target and block DNA repair in cancer cells. Other gynecologic cancers may be treated with therapies targeting the PI3K/AKT/mTOR or angiogenesis pathways, depending on the tumor's profile.²⁶

Other Solid Tumors

Several other solid tumors may respond to targeted therapies if they carry actionable mutations:

• Kidney (renal cell carcinoma): VEGF inhibitors (sunitinib, axitinib) block angiogenesis²⁷
• Liver (hepatocellular carcinoma): Multi-kinase inhibitors like sorafenib or lenvatinib disrupt growth signaling²⁸
• Stomach and pancreatic cancers: HER2-targeted therapy or TRK inhibitors can be effective in patients with specific molecular alterations²⁹

Personalized genomic testing is key for identifying druggable targets in all solid tumors³⁰

Advantages and Challenges of Targeted Therapy

Targeted therapies can significantly improve treatment outcomes in cancer. Because they act on specific mutations and pathways, their damage to healthy tissues is considerably less than that of conventional chemotherapy. Therefore, patients often experience fewer severe side effects, such as hair loss, nausea or immune suppression, leading to better tolerance and quality of life. By directly attacking the biological drivers of tumor growth, targeted therapies can achieve higher response rates and prolonged survival in patients with biomarker-positive cancers. In precision medicine, they can be tailored to individual profiles or combined with other anti-cancer modalities to achieve optimum efficacy.^1,30

Nevertheless, targeted therapies may present additional challenges. Drug resistance is a common occurrence, where tumors develop additional mutations or compensatory signaling loops to reactivate pathways that have been inhibited. Therefore, drug resistance may limit long-term effectiveness and result in patient relapse. Another challenge is the high cost of targeted therapies, largely due to the complexity of their development and manufacturing processes. Accessibility can be limited in healthcare settings, particularly in underprivileged communities. Moreover, these therapies are only effective in patients whose tumors carry specific molecular alterations. Patient selection often requires comprehensive genomic profiling and biomarker testing, which may not always be accessible or affordable.³¹

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