Oncogenes

Oncogenes are genes that upon malfunctioning may cause cancer. These are genes related to cell growth and cell proliferation and are tightly controlled within the healthy cell and organism. When they mutate, oncogenes stop participating in a controlled manner in the cell cycle. This leads to uncontrolled cell growth and cell proliferation which are hallmarks of cancer.

Approximate frequency of RAS mutations in human cancers.

There are different types of oncogenes leading 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).

Cancer Type% KRAS% NRAS% HRAS% All RAS
Pancreatic adenocarcinoma90-980-0.5091-98
Colorectal adenocarcinoma40-454-8044-53
Multiple myeloma2219042
Lung adenocarcinoma16-330.6-0.90.3-0.517-33
Skin cutaneous melanoma0.828129
Biliary carcinoma253027
Uterine endometroid carcinoma14-212-30.4-0.516-25
Small intestine adenocarcinoma230.7023
Chronic myelomonocytic leukemia913022
Thyroid carcinoma1-26-9413-14
Acute myeloid leukemia3-47-11211-15
Cervical adenocarcinoma7-80.80-67-15
Urothelial carcinoma3-41-26-911-15
Stomach adenocarcinoma6-1110-19-12
Head and neck squamous cell carcinoma0.5-20.3-25-65-10
Gastric carcinoma4.0-610-15-9
Esophageal adenocarcinoma2-400.6-0.73-5

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/indicationInhibitor(s)Observed clinical responses
BCR-ABL mutant CMLImatinib, nilotinib, dasatinib, ponatinibComplete cytogenetic responses: 65–80% 9, 112, 113, 166
KIT mutant GISTImatinib53.7% partial response in patients with refractory disease 170
BRAF mutant melanomaVemurafenib, dabrafenib45–51% response rate; benefits observed versus prior standard of care 58, 59, 173
EGFR mutant NSCLCGefitinib, erlotinib, afatinib9–13 months progression-free survival; 73.7% response rate for gefitinib; benefit versus standard chemotherapy 178, 179, 180, 181, 182
EGFR-amplified colorectal cancerCetuximab, panitumumabImprovements in progression-free survival versus best supportive care 187
ALK-translocated NSCLCCrizotinib, ceritinib, alectinib55–65% response rate; improved response rate versus standard chemotherapy 116, 117, 188
HER2/ERBB2-amplified breast cancerTrastuzumab, lapatinib, pertuzumabTrastuzumab: 33% combined complete and partial response rate 193; Lapatinib: 39% partial response rate 194
ROS1-translocated NSCLCCrizotinib72% objective response rate 197
RET mutant medullary thyroid carcinoma (MTC)Vandetanib46% objective response rate in patients with hereditary MTC harboring RET mutation 199
Retinoic acid receptor (RARA)-translocated APLATRAComplete response rates of > 90%; superior to prior chemotherapy regimens 200
AR-positive castration-resistant prostate cancerEnzalutamide18.4-month overall survival, 54% PSA reduction 202
ER-positive metastatic breast cancerTamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestaneTamoxifen: approximately 50% drop in mortality with 10 years of treatment 204

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.

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