What Is Oncogenic Addiction in Cancer Cells?

What is targeted therapy for oncogenic addiction in cancer?

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:

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

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:

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:

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:

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:

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: