You probably are somewhat aware of this disease. Cancer, an umbrella term for the more than 200 types of cancers, might likely be the disease that you would not even wish upon your worst enemies. With an estimated number of 1.9 million new cancer cases and 609,360 cancer deaths in the United States, cancer holds its position as the 2nd most common cause of death, after heart disease. However, cancer researchers might have found a breakthrough in the form of Sotorasib.
After 40 years of extensive research, Sotorasib promises an effective therapy in non-small cell lung cancer treatment. Generally, lung cancer is divided in two categories: small cell and non-small cell lung cancer (to be further referred as NSCLC) . The cancer type in question accounts for 85% of all lung cancer cases in the United States. Remarkably, NSCLC can occur in both smokers and non-smokers (10-15% of NSCLC patients) and has multiple subcategories. Essentially, this new drug will be able to target a specific gene mutation in NSCLC, known as KRAS G12C. This mutation has for decades widely been acknowledged as ‘aggressive’ and ‘undruggable’ due to its intrinsic or acquired resistance caused by cellular, molecular and genetic mechanisms.
Let’s first review the molecular profile of KRAS G12C. Kirsten rat sarcoma, KRAS, is the most common gene that has the potential to develop cancer. These kinds of genes are known as oncogenes, onco meaning related to cancer/tumours. In normal circumstances, a healthy KRAS protein sends a message to signal cell growth. In the case of a mutated KRAS, the protein becomes hyperactive and continues growing uncontrollably. Thus, transmitting too many growth signals to the (now) cancer cell. This specific type of KRAS, namely G12C, accounts for 13% of all NSCLC cases. KRAS G12C is a point mutation at codon 12 that causes a substitution of glycine (GLY) to cysteine (CYS). This substitution impairs GTP hydrolysis (which is involved in the regulation of cellular processes, such as cell growth) and keeps the KRAS protein ‘switched on’ in an active state, resulting in oncogenesis.
This novel drug, Sotorasib, hinders the uncontrollable activation of KRAS G12C by basically binding to the mutated protein, rendering it inactive. This inactive structure of KRAS G12C will subsequently not be able to transmit any growth signals. The drug also promotes apoptosis (programmed cell death), resulting in the elimination of the cancel cell. The CodeBreaK 100 Phase 2 clinical trial showed the effectiveness of this drug on 126 KRAS G12C-mutated NSCLC patients. Most of the patients had previously received immunotherapy or chemotherapy. The study group was commanded to take Sotorasib in the form of an oral pill once a day for a median of 15 months. Statistically, the tumour completely shrank in 3% of the patients, partially shrank in 36% of the patients, was stable in 44% of the patients and progressed in 16% of the patients. Moreover, the drug kept the cancer at bay for approximately 7 months. This is a promising sight, as standard therapies provide short-lived effects and ‘only’ shrink tumours in less than 20% of KRAS G12C-mutated NSCLC patients.
Furthermore, various combinations of Sotorasib with other substances that also inhibit certain processes in the signaling pathways associated with cell growth are currently being tested. This is based on the hope of ‘avoiding or at least delaying the development of resistance’, as tumour cells can become accustomed to the treatment and adapt to its effect(s). Additionally, a combination of Sotorasib with immunotherapy in the form of checkpoint inhibitors could reactivate the immune system and promote the body’s defense against the cancer while weakening the tumour cells.
Overall, this new drug brings diverse possibilities to light for non-small lung cancer treatment while providing patients a progression-free survival with better life quality. Moreover, Sotorasib could also be an option for other cancer types, as the KRAS G12C mutation is also present in colon carcinomas and pancreatic carcinomas. With all the rapid development and breakthroughs, we might be able to completely cure certain cancer types in the near future.
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