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.
Different types of oncogenes lead to different cancers. Ras is a typical oncogene. Ras proteins control cell growth and are cycle between ‘ON’ and ‘OFF’ modes, tightly regulated by molecular pathways. Ras mutations are the most common and lead to at least 17 different types of cancer, including colorectal and lung cancers. Cell growth and proliferation are promoted and apoptosis (programmed cell death) is inhibited. Cellular machinery that is adapted to cell growth is switched on, aiding the uncontrolled expansion of tumor cells (Palayeva-Gupta, 2011).
Approximate frequency of RAS mutations in human cancers.
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 novel oncogene BCR-ABL fusion gene. Novartis is developing an inhibitor of the BCR-ABL kinase which successfully got through phase I clinical trials (Maughan, 2017). This pattern could be used in other areas: the specific type of oncogene involved in the cancer would inform development of therapies against specific types 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 is a limitation of treatment by approaching oncogene addiction. Many cancers, when treated with drugs inhibiting addicting oncoproteins, develop resistance to kinase inhibitors, making them impossible to respond to treatment. Cancer heterogeneity remains a profound challenge even when deploying personalized medicine approaches targeting addicting oncoproteins.
Understanding of the type of oncogene mutation involved in a particular type of cancer helps doctors customize the treatment plan, using personalized medicine approaches. This is important since Ras inhibitors may not be important in cancers involving mutations of tumor suppressor genes, that also may lead to cancer. Sequencing of tumors using liquid or solid biopsies is part of deciding on the personalized treatment regime.
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 would be sufficient for cancer treatment (Luo et al., 2009). This is because oncogenes are most frequently genes that produce proteins that are rate-limiting in a pathway. The hypothesis has been clinically validated, as therapy targeting oncogenes responsible for oncogene addiction has been very successful. In CML, addiction to BCR-ABL mutant oncogene was found to be profound and the 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 of treatment by addressing oncogene addiction. 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 involved in DNA repair can be oncogenes. Genes that regulate growth factors and growth factor receptors as well as genes involved in mitosis and cell division are candidates for oncogenes.
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