Targeted Therapies for Uncommon Oncological Mutations

Introduction:

Targeted therapy is a form of cancer treatment that uses specific drugs to attack the genes and proteins that help cancer cells thrive and multiply. It can impact the environment where cancer cells grow or target cells connected to cancer growth, such as blood vessel cells. This treatment can be applied to various types of cancer and may be combined with other treatments like chemotherapy. While not all cancers have targeted therapies, ongoing research explores and develops new options in this field. This article explains the fundamental workings of targeted therapy in cancer treatment.

What Are the Oncological Mutations of Lung Cancer?

EGFR Mutations in Lung Cancer:

• The EGFR (Epidermal Growth Factor Receptor) gene is a key player in non-small cell lung cancer (NSCLC). Mutations in EGFR can promote cancer growth.

• EGFR mutations are more common in certain groups, such as non-smokers, Asians, and females, and are mostly found in adenocarcinomas.

• Several drugs, known as EGFR tyrosine kinase inhibitors (TKIs), have been developed to target EGFR mutations in NSCLC.

• The majority of patients with EGFR mutations have either an exon 19 deletion or the exon 21-point mutation L858R.

• Despite initial responses to TKIs, patients can develop resistance, often due to secondary mutations like T790M.

• Newer drugs like Osimertinib target these resistant mutations and other uncommon EGFR mutations.

• Some patients have EGFR exon 20 insertion mutations, which are more challenging to treat. Drugs like Mobocertinib and amivantamab have shown promise.

• Some patients develop resistance independent of EGFR mutations, often involving other genetic changes, like MET amplification, KRAS mutations, or BRAF mutations.

• HER2 mutations are less common but still important. Some drugs, including trastuzumab Deruxtecan, are being explored for HER2-mutated NSCLC.

KRAS Mutations in Lung Cancer:

• KRAS mutations are common in NSCLC, and the most prevalent is KRAS-G12C.

• Drugs like Adagrasib and Sotorasib have shown promise in treating KRAS-G12C mutations.

• Some patients develop resistance to these drugs, often due to secondary KRAS mutations or other genetic changes.

• Research is ongoing to identify more targets and develop therapies for KRAS-mutated NSCLC.

MET Mutations or Amplification in Lung Cancer:

• MET alterations, including skip mutations, occur in a small percentage of NSCLC.

• Drugs like Crizotinib, Capmatinib, and Tepotinib have effectively treated MET-altered NSCLC.

• Some patients develop resistance to these therapies, often involving genetic alterations or bypass signaling.

• Ongoing research aims to understand resistance mechanisms better and improve treatment for MET-altered NSCLC.

BRAF Mutations in Lung Cancer:

• BRAF mutations are found in a small percentage of NSCLC, with the V600E mutation being the most common.

• A combination of drugs, such as trametinib and dabrafenib, has shown promise in treating BRAF-mutated NSCLC.

• Resistance mechanisms to BRAF inhibitors are poorly understood, and further research is needed.

• Research continues to explore new treatments for BRAF-mutated NSCLC.

What Are the Targeters Therapies for Different Types of Cancer?

Cancer researchers are working on new treatments targeting the mechanisms driving cancer growth. Here are some examples of targeted therapies for different types of cancer:

1. Breast Cancer: In some cases, breast cancer cells have a protein called HER2 that makes them grow. Targeted therapies can block this protein and help slow down the cancer.

2. Chronic Myeloid Leukemia (CML): CML is often caused by a specific gene called BCR-ABL, which produces a problematic enzyme. Targeted therapy can inhibit this enzyme and stop the disease from progressing.

3. Colorectal Cancer: Colorectal cancer cells often overproduce a protein called EGFR, which helps them grow. Drugs can block EGFR and slow down cancer growth. Some treatments focus on other genetic changes.

4. Lung Cancer: For Non-Small Cell Lung Cancer (NSCLC), there are various targeted therapies available. These drugs target specific genetic changes in the cancer cells, such as EGFR inhibitors, ALK inhibitors, and drugs for other mutations.

5. Lymphoma: In lymphoma, there is an excess of certain white blood cells called B cells. Targeted drugs can block the enzyme responsible for this overproduction, effectively treating lymphomas and some B-cell leukemias.

6. Melanoma: Many melanomas have a genetic mutation in the BRAF gene, making it a good target for therapy. There are drugs known as BRAF inhibitors that specifically target this mutation. MEK inhibitors are also used in melanoma treatment, and sometimes, these drugs are combined.

What Are the Benefits of Targeted Therapy?

Targeted therapies work in different ways to fight cancer based on what we want to achieve with the treatment. They can:

• Stop signals that make cancer cells grow.

• Change proteins in cancer cells to make them die.

• Block the creation of new blood vessels that feed the tumor.

• Activate your immune system to fight the cancer.

• Deliver harmful substances that specifically kill cancer cells without hurting normal ones.

What Are the Side Effects of Targeted Therapy?

Despite the hope that targeted cancer therapies would be gentler than traditional chemotherapy, they can still have significant side effects.

• The side effects from targeted therapies can be different from those of chemotherapy and depend on how each therapy works.

• Patients might experience these side effects, such as bleeding, and oncologists may seek help from regular doctors to manage ongoing issues, such as high blood pressure.

• Some targeted therapies, like EGFR inhibitors, often cause skin problems like rash, nail changes, hair color changes, dry skin, and yellowing.

• Preventive measures and guidelines are available to manage these skin issues.

• Trastuzumab, on the other hand, can lead to congestive heart failure.

• Targeted therapies focused on VEGF (Vascular Endothelial Growth Factor) may result in side effects such as high blood pressure, blood clotting problems, slower wound healing, and a higher risk of bleeding, including bleeding from tumors.

Treatment for Side Effects:

How side effects are handled depends on how bad they are. When they are not too severe, mild ones can often be managed by treating the symptoms. If the effects are moderate, it might be necessary to take a break from treatment or lower the dose. But when side effects are very serious, it's more likely that the treatment causing them will need to be stopped, and doctors will search for other treatment options.

How Does Gene Mutation Contribute to Improving Cancer Treatment?

New research published in PLOS Computational Biology reveals a novel approach to understanding how genetic mutations contribute to cancer growth. Typically, cancer starts when genetic mutations lead to abnormal cell growth. These mutations can prompt the development of tumors. Existing cancer treatments often target known mutations, but many remain undiscovered.

Researchers at the University of Maryland used a new statistical method to identify hidden mutations shared by families of related proteins, focusing on mutations occurring in specific regions called protein domains. These domains are like functional units within proteins. By studying mutations in these shared regions across proteins, the researchers uncovered thousands of rare tumor mutations that appear to be linked to cancer.

These specific regions with mutations are referred to as "oncodomains." Understanding Oncodomains could lead to more effective cancer treatments, as a single treatment could address cancers caused by various mutated proteins that share these oncodomains. This research provides a promising new avenue for improving cancer treatment by exploring the genetic basis of cancer from a different perspective, potentially revealing new targets for drug development.

Conclusion:

With more people being diagnosed with cancer and new treatment options becoming available, family doctors may need to assist patients in understanding these treatments. They must know how targeted therapy functions, why certain treatments are suitable, and what side effects to expect. This knowledge helps patients in their cancer treatment journey.