Targeted Therapy: What Is Oncogenic Addiction in Cancer Cells?

Targeted therapy is a specialized cancer treatment that targets specific cancer-causing proteins and mechanisms in the cellular level. Targeted cancer therapy uses medications that alter the way cancer cells function to inhibit their abnormal growth.

When a tumor relies heavily on one mutated gene to keep growing and spreading, this is called oncogenic addiction. Certain therapies target these mutated genes (oncogenes) necessary for tumor growth and aim to stopping the genetic activity of that gene. Ideally, this strangles the tumor and keeps it from growing further.

Targeted cancer therapy is administered with two primary types of medications:

• Small molecule drugs: Small molecule drugs are tiny particles that can work on the surface of the cells and can also get into the cell and work on the proteins and signaling pathways inside the cancer cell.
• Monoclonal antibodies: Monoclonal antibodies are lab-made protein molecules that are too large to get inside a cell. Monoclonal antibodies attach to proteins on the cancer cell surface and work by activating the immune system

Cancer is a unique group of diseases caused by abnormal growth of cells due to certain defects. The life cycle of a normal cell in the human body is strictly regulated by several mechanisms which instruct the cells when to grow, divide, differentiate or die. Cancer cells have flawed genetic material which helps them evade these mechanisms to grow uncontrollably.

Cancers arise due to several reasons such as genetic mutations, environmental factors, certain viral infections, and sometimes for no apparent reason. Cancers can develop in any part of the body and ultimately spread all over the body (metastasis).

Genetic mutation is the alteration in genetic material that occurs during cell division. The human genetic material consists of 23 pairs of chromosomes which contain the DNA, proteins, and genes that encode the growth and function of each human cell.

When activated by growth factor proteins, cells grow and divide by making exact copies of the chromosomes for every new cell. Errors often occur in copying the DNA, and mostly, the inhibitory mechanism in the cells identifies faults in the DNA, stops the dividing process, and destroys the defective cell.

But some cells defy this process, carry on the mutation and continue growing and dividing. Many of the mutations are harmless and sometimes even beneficial. But some genetic mutations can lead to serious illnesses. Cancer is primarily caused by mutations in two classes of genes:

• Proto-oncogenes: Genes that enhance growth and development.
• Tumor suppressor genes: Genes that inactivate mutated genes.

Oncogenes are genes that have high potential to cause cancer, and a leading reason for cancer. Oncogenes are the mutated form of proto-oncogenes which play an essential role during embryonic development and tissue growth.

Proto-oncogenes instruct (encode) proteins that stimulate growth and division of cells, inhibit differentiation (maturation of a cell with a specialized function) and stop cell death (apoptosis).

Proto-oncogene activity is normally turned off once the development process is complete. Mutations in proto-oncogenes turn them into oncogenes which continue to remain active and cause unrestrained cell growth leading to cancer.

Usually there are several overlapping reasons for cancer. Continued division of defective cells leads to multiple genetic mutations, and all of them further contribute to cancer cell growth and proliferation. 

Research indicates that cancer cells may rely more heavily on oncogenic mutations that originally gave rise to the particular cancer, rather than other reasons for their growth. Such cancers are termed to have an oncogenic addiction to the particular oncogene, because they mainly depend on that oncogene’s continued activity for survival.

Targeted therapy for oncogenic addiction involves identification of the oncogene specific to a cancer and inhibiting the activity of the proteins it encodes. Most of the targeted therapies for oncogenic addiction are small-molecule inhibitors, which bind to cell proteins and block their activity.

Targeted therapy may be administered as a monotherapy or in combination with chemotherapy.

Following are some of the oncogenic addictions found in cancers and therapies that target them:

BCR-ABL

BCR-ABL is an oncogene resulting from the fusion of two genes (BCR and ABL), because of a switch in their positions in the chromosomes. The chromosome with BCR-ABL oncogene is called the Philadelphia chromosome.

The BCR-ABL mutation leads to unregulated activity of a protein known as tyrosine kinase. Tyrone kinase activates uncontrolled growth and division of cells with this mutation. There are several mutant forms of BCR-ABL. BCR-ABL oncogene causes:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL), rarely

Following are some of the small molecule inhibitors that target BCR-ABL oncogenic addiction:

• Imatinib mesylate
• Nilotinib
• Dasatinib
• Bosutinib

Many BCR-ABL mutations develop resistance to drugs. Novel formulations to combat these resistant mutations are in clinical development.

c-KIT/PDGFR

Mutations in the proto-oncogene c-KIT, and a growth factor known as ‘platelet-derived growth factor receptor’ (PDGFR) lead to several types of malignancies including:

• Gastrointestinal stromal tumor
• Hypereosinophilic syndrome
• Systemic mastocytosis
• Dermatofibrosarcoma protuberance
• Chronic myelomonocytic leukemia (CMML)

Targeted therapies for c-KIT/PDGFR driven cancers are:

• Imatinib mesylate
• Sunitinib malate.

HER family of genes

HER (human epidermal growth factor receptor) family with four types of proto-oncogenes (HER1 to HER4) were the first to be selected for targeted therapy. HER family of genes encode HER proteins which activate cell-signaling pathways inside the cell enabling cell growth and division.

HER1 and HER2 growth factors switch on an important protein known as RAS in the cell membrane which activates a cascade of downstream cell-signaling pathways which stimulate cell growth, division and differentiation. HER growth factors also activate other cell-signaling pathways that assist in cell growth.

Mutations and amplification of the HER2 gene can lead to excessive presence (overexpression) of HER2 proteins on the cell surface, a major cause for breast cancer. Cancers caused by HER oncogenes include:

• HER2 positive breast cancer
• Non-small-cell lung carcinoma
• Glioblastoma multiforme
• Head and neck cancers
• Prostate cancer
• Metastatic stomach cancer
• Colon cancer
• Pancreatic cancer
• Ovarian cancer

Non-HER2 breast cancers cannot be treated with targeted therapy. 

Following are the FDA-approved monoclonal antibodies for HER oncogenic addiction:

• Trastuzumab (Herceptin) for HER2 positive breast cancer
• Trastuzumab-dkst (Ogivri) for HER2 positive metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma)
• Trastuzumab-pkrb (Herzuma) for HER2 overexpressing breast cancer
• Pertuzumab for HER3 overexpressing tumors of ovary, prostate, breast, colon and lung
• Cetuximab for HER1 mutation cancers of colon, head and neck
• Panitumumab for HER1 specific cancers of colon, head and neck
• The FDA-approved small molecule drugs include the following:
• Erlotinib (Tarceva) for HER1 specific non-small-cell lung carcinoma and metastatic pancreatic cancer
• Gefitinib (Iressa) for HER1 specific non-small-cell lung carcinoma
• Lapatinib ditosylate (Tykerb) for HER1/HER2 breast cancer resistant to trastuzumab

More HER-targeted therapies are under clinical trials.

c-MET

MET is the gene that encodes a protein, c-MET, which activates many signaling pathways enabling new blood vessel formation (angiogenesis), cell mobility, migration and invasion. A mutation in the MET gene can help the tumor build up its own blood supply and enables cells to break off from the tumor, migrate, invade and metastasize.

Researchers have observed MET oncogene’s involvement in lab studies of many cancers including:

• Osteosarcoma
• Papillary renal cell carcinoma
• Gastric cancer
• Lung cancer

Therapies to target c-MET are in the clinical trial stage.

PI3K/AKT

PI3K/AKT are a family of enzymes encoded by PIK3CA gene. PI3K/AKT enzymes play an important role in cell-signaling for cell division, differentiation and migration. Mutations in PIK3CA gene help tumor growth by promoting these activities in the tumor cells.

Many therapies targeting PI3K/AKT signaling pathways are in various stages of development.

RET (c-RET)

The RET proto-oncogene is involved in cellular mechanisms that include cell proliferation, nerve cell navigation to their appropriate position in the nerves, cell migration and cell differentiation.

Mutations in RET proto-oncogene cause hereditary and sporadic (other than hereditary factors) medullary thyroid carcinoma (MTC). Beside familial medullary thyroid carcinoma, RET mutations also cause other tumors and disorders such as:

• Pheochromocytoma
• Ganglioneuroma
• Primary hyperparathyroidism
• Marfan syndrome

Several targeted therapies directed at c-RET are in clinical trials. Some of the c-RET targeted therapies have also shown effect against other proteins involved in cell proliferation and angiogenesis in tumors.

B-RAF

B-RAF is a protein kinase found inside the cell and plays a key role in cell proliferation and transformation (that is, the cell’s transition from healthy to cancerous). B-RAF is encoded by BRAF proto-oncogene. BRAF mutations have been found in cancers such as:

• Melanoma
• Papillary thyroid carcinoma
• Colorectal cancer
• Non-small-cell lung carcinoma
• Renal cell cancer
• Hepatocellular cancer

BRAF mutations are found to frequently occur in many cancers, and many kinase inhibitors are in clinical trials specifically targeting B-RAF kinase. Currently there is only one FDA-approved small molecule drug which targets many other oncogenes besides BRAF:

• Sorafenib, approved for renal cell and hepatocellular cancers

ALK

Anaplastic lymphoma kinase (ALK) encoded by ALK gene is a receptor tyrosine kinase protein which plays a role in nerve cell differentiation and regeneration, formation of synapses (micro spaces linking nerve cells to one another) and muscle cell migration.

Translocation of ALK gene in the chromosome causes fusion with other genes, giving rise to an ALK fusion gene. Different mutations of ALK fusion oncogene have been found to cause cancers that include:

• Anaplastic large cell lymphoma
• Inflammatory myofibroblastic tumor
• Non-small-cell lung cancer

Therapies targeting ALK protein are in the early phase of clinical trials as of 2020.

TRK

Tropomyosin receptor kinase (TRK) proteins include TRKA, TRKB and TRKC encoded by neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2 and NTRK3, respectively. TRP proteins are involved in cell survival and proliferation.

Mutations due to chromosomal fusion in the NTRK genes have been identified in many solid tumors. FDA has approved one targeted therapy for TRK-fusion-positive solid tumors in adults and children:

• Larotrectinib