Oncogenes

Oncogenes are genes that when they malfunction can cause cancer. These genes are related to cell growth and cell proliferation and are tightly controlled within the healthy cell and organism. When they mutate, oncogenes stop participating in the cell cycle the way they should. This leads to uncontrolled cell growth and cell proliferation which are hallmarks of cancer.  The first oncogene discovered was a protein kinase.  Sometimes the words oncogene and proto-oncogene are used interchangeably.  In this terminology, the proto-oncogene is a normal gene that could become an oncogene if it mutates or somehow starts expressing more.

Cancer Type % KRAS % NRAS % HRAS % All RAS
Pancreatic adenocarcinoma 90-98 0-0.5 0 91-98
Colorectal adenocarcinoma 40-45 4-8 0 44-53
Multiple myeloma 22 19 0 42
Lung adenocarcinoma 16-33 0.6-0.9 0.3-0.5 17-33
Skin cutaneous melanoma 0.8 28 1 29
Biliary carcinoma 25 3 0 27
Uterine endometroid carcinoma 14-21 2-3 0.4-0.5 16-25
Small intestine adenocarcinoma 23 0.7 0 23
Chronic myelomonocytic leukemia 9 13 0 22
Thyroid carcinoma 1-2 6-9 4 13-14
Acute myeloid leukemia 3-4 7-11 2 11-15
Cervical adenocarcinoma 7-8 0.8 0-6 7-15
Urothelial carcinoma 3-4 1-2 6-9 11-15
Stomach adenocarcinoma 6-11 1 0-1 9-12
Head and neck squamous cell carcinoma 0.5-2 0.3-2 5-6 5-10
Gastric carcinoma 4.0-6 1 0-1 5-9
Esophageal adenocarcinoma 2-4 0 0.6-0.7 3-5

From: Scott at al. (2016)

Chronic myeloid leukemia can be caused by mutations in the oncogene BCR-ABL fusion gene. Drugs that inhibit the BCR-ABL kinase have been developed and are in use today. Drugs developers are attempting to follow this pattern in other areas: the specific type of oncogene involved in the cancer would inform development of therapies against that type of cancer, or a broader treatment (especially if Ras is targeted). So far, there is no successful therapeutic approach targeting Ras (Scott et al., 2016). Several are in clinical trials, especially inhibitors of Ras downstream effectors. Novartis and AstraZeneca belong among the pharmaceutical companies researching the use of Ras inhibitors in cancer.

However, resistance limits this type of treatment. Many cancers, when treated with drugs inhibiting addicting oncoproteins, develop resistance to the drugs. Cancer heterogeneity remains a profound challenge when developing personalized medicine approaches by targeting addicting oncoproteins.

Understanding the type of oncogene mutation involved in a particular type of cancer helps doctors customize the treatment plan. Sequencing the genomes of tumor cells can tell the doctors which mutations are present in the cancer.

Oncogene addiction theory suggests that some cancers rely on a single oncogene for growth and survival. This theory also postulates that inhibition of this single oncogene is sufficient for cancer treatment (Luo et al., 2009). This is because the oncogenes often produce proteins that are rate-limiting in a biochemical pathway.  The end of this pathway is a factor leading to cell growth or differentiation.  Inhibiting oncogenes is thought to be a way that signal transduction inhibitors work,  The hypothesis has been clinically validated, as therapy targeting oncogenes responsible for oncogene addiction has been very successful. Chronic myeloid leukemias are addicted to BCR-ABL mutant oncogene.  Clinical response to BCR-ABL inhibitor imatinib showed overwhelmingly positive response (Pagliarini et al., 2015). Other examples of oncogene-targeted therapies are listed below for different cancers:

Examples of approved oncogene-targeted therapies and observed resistance mechanisms in patients

Target/indication Inhibitor(s) Observed clinical responses
BCR-ABL mutant CML Imatinib, nilotinib, dasatinib, ponatinib Complete cytogenetic responses: 65–80%
KIT mutant GIST Imatinib 53.7% partial response in patients with refractory disease
BRAF mutant melanoma Vemurafenib, dabrafenib 45–51% response rate; benefits observed versus prior standard of care
EGFR mutant NSCLC Gefitinib, erlotinib, afatinib 9–13 months progression-free survival; 73.7% response rate for gefitinib; benefit versus standard chemotherapy
EGFR-amplified colorectal cancer Cetuximab, panitumumab Improvements in progression-free survival versus best supportive care
ALK-translocated NSCLC Crizotinib, ceritinib, alectinib 55–65% response rate; improved response rate versus standard chemotherapy
HER2/ERBB2-amplified breast cancer Trastuzumab, lapatinib, pertuzumab Trastuzumab: 33% combined complete and partial response rate; Lapatinib: 39% partial response rate
ROS1-translocated NSCLC Crizotinib 72% objective response rate
RET mutant medullary thyroid carcinoma (MTC) Vandetanib 46% objective response rate in patients with hereditary MTC harboring RET mutation
Retinoic acid receptor (RARA)-translocated APL ATRA Complete response rates of > 90%; superior to prior chemotherapy regimens
AR-positive castration-resistant prostate cancer Enzalutamide 18.4-month overall survival, 54% PSA reduction
ER-positive metastatic breast cancer Tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane Tamoxifen: approximately 50% drop in mortality with 10 years of treatment

From: Pagliarini et al. (2015)

Protein kinase inhibitors play a major role in therapeutic regimens targeting downstream effectors of genes central to oncogene addiction (Sharma and Settleman, 2007). A theory involving oncogenic shock has been proposed and may inform selection of drug combinations for cancer therapy. Traditional chemotherapy drugs inhibit cell cycle progression (reproduction) and need to be considered when used together with drugs inhibiting addicting oncoproteins. This is because inhibition of addicting oncoproteins triggers cell cycle-dependent apoptosis. Progression through the cycle will be important when deploying therapy targeting addicting oncoproteins.

However, resistance is a limitation in drug treatment. Cancer heterogeneity remains a profound challenge even when deploying personalized medicine approaches targeting addicting oncoproteins.

Oncogenes normally function in cellular processes such as cell division, apoptosis, and differentiation. When they mutate they can directly contribute to the formation of tumors.  Genes that regulate growth factors and growth factor receptors as well as genes involved in mitosis and cell division can oncogenes.  Genes involved in DNA repair can be oncogenes, too.

REFERENCES

Maughan, T., 2017. The Promise and the Hype of ‘Personalised Medicine.’ New Bioeth 23, 13–20. https://doi.org/10.1080/20502877.2017.1314886

Pagliarini, R., Shao, W., Sellers, W.R., 2015. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep 16, 280–296. https://doi.org/10.15252/embr.201439949

Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction: Cell [WWW Document], n.d. URL https://www.cell.com/cell/fulltext/S0092-8674(09)00200-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867409002001%3Fshowall%3Dtrue (accessed 5.27.20).

Pylayeva-Gupta, Y., Grabocka, E., Bar-Sagi, D., 2011. RAS oncogenes: weaving a tumorigenic web. Nature Reviews Cancer 11, 761–774. https://doi.org/10.1038/nrc3106

Scott, A.J., Lieu, C.H., Messersmith, W.A., 2016. Therapeutic Approaches to RAS Mutation. Cancer J 22, 165–174. https://doi.org/10.1097/PPO.0000000000000187

Sharma, S.V., Settleman, J., 2007. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 21, 3214–3231. https://doi.org/10.1101/gad.1609907