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How Does Targeted Therapy for Lung Cancer Work?

Posted on April 12, 2022
Medically reviewed by
Richard LoCicero, M.D.
Article written by
Emily Wagner, M.S.

Lung cancer therapies work in a variety of ways. Some treatments, such as chemotherapy, are known as systemic treatments because they affect the entire body. Another type of treatment used for lung cancer is targeted therapies.

Targeted therapies work more specifically on certain proteins found in certain cells. These medications are mainly used to treat non-small cell lung cancer (NSCLC). This type of lung cancer is caused by specific mutations in DNA that provide targets for the medication.

Currently, only advanced cases of NSCLC are being treated using targeted therapies. Many people on these therapies have tried standard treatments such as chemotherapy and radiation therapy. In some cases, targeted therapies are given with chemotherapy to help shrink tumors.

What Makes a Good Target Protein?

To target lung cancer cells, targeted therapies must be able to zero in on proteins specific to cancer cells. Many gene mutations found in lung cancer are in a specific set of proteins known as receptor tyrosine kinases (RTKs). These proteins sit on the outside of cells. When a growth factor binds to them, they send signals for cell growth and division. After the signal has been sent, the receptors turn off and wait for more growth factors to bind.

In lung cancer, mutations in the genes that code for RTKs create mutated proteins. Many times, these mutations create RTKs that send growth signals to cells even when growth factors are not bound to them. This causes the cells to grow and divide uncontrollably because there is no way to shut them off.

Some people’s cancer cells may also have too many copies of the genes that make RTK proteins. This means that the cells have too many receptors on their surface, so they send too many growth signals inside the cells to grow and divide.

When cells grow and divide uncontrollably, they can create new mutations in the DNA. Eventually, the cells will have too many mutations and become cancerous.

Tyrosine Kinase Inhibitors

Researchers have developed targeted therapies that work only on specific RTKs that may be mutated in lung cancer. These medications are known as tyrosine kinase inhibitors (TKIs). They work by blocking the receptor from sending growth signals, which can help shrink tumors.

Targets in Lung Cancer

Several types of RTKs in lung cancer can be mutated. These mutated RTKs then become targets for therapy in people whose cancer cells make these proteins. NSCLC cases are most often caused by these mutations, so targeted therapy is generally recommended for treatment.

EGFR

Epidermal growth factor receptor (EGFR) is an RTK that signals to cells to grow and divide when it interacts with epidermal growth factor (EGF). EGFR mutations are found in 10 percent to 15 percent of lung cancer cases.

TKIs have been developed that interrupt the growth signals that EGFR sends inside of cells. Some of the drugs bind permanently to the receptor, which can cause the tumor cells to die. TKIs for EGFR mutations include:

  • Afatinib (Gilotrif)
  • Erlotinib (Tarceva)
  • Dacomitinib (Vizimpro)
  • Gefitinib (Iressa)

Osimertinib (Tagrisso) is used when a person’s cancer becomes resistant to EGFR inhibitors. This is most likely caused by the EGFR protein gaining a new mutation known as T790M.

Two synthetic antibody drugs (known as monoclonal antibodies) have also been developed to treat NSCLC with EGFR mutations. Amivantamab (Rybrevant) binds to two RTKS — EGFR and MET — to stop them from signaling to cells. Necitumumab (Portrazza) is given to people with EGFR mutations and a specific type of NSCLC known as advanced squamous cell NSCLC.

ALK

Anaplastic lymphoma kinase (ALK) is another RTK that can be mutated in NSCLC. ALK mutations are found in around 5 percent of NSCLC cases. TKIs have been developed to stop ALK from sending signals to cells for growth and division. They include:

  • Alectinib (Alecensa)
  • Ceritinib (Zykadia)
  • Lorlatinib (Lorbrena)
  • Crizotinib (Xalkori)
  • Brigatinib (Alunbrig)

BRAF

BRAF is an enzyme found inside cells that is responsible for signaling growth and division. It is mutated in around 4 percent of NSCLC cases. BRAF is a member of a family of similar enzymes known as MAP kinases. Targeted therapies for BRAF and other proteins have been developed, including:

  • Dabrafenib (Tafinlar), which binds directly to BRAF to block it from sending signals
  • Trametinib (Mekinist), which works on the related protein MEK

ROS1

ROS1 is another gene that mutates in some cases of NSCLC. ROS1 mutations are similar to ALK mutations. Because of this similarity, many TKIs used to treat ALK mutations can also treat ROS1 mutations, and vice versa. These drugs include:

  • Entrectinib (Rozlytrek)
  • Crizotinib (Xalkori)
  • Lorlatinib (Lorbrena)
  • Ceritinib (Zykadia)

NTRK

NTRK is a growth receptor that is rarely mutated in NSCLC cases. TKIs have been developed that stop the receptor from sending growth signals. They include larotrectinib (Vitrakvi) and entrectinib (Rozlytrek).

KRAS

KRAS mutations are common in NSCLC, occurring in roughly 25 percent of all cases. One specific mutation, KRAS G12C, is found in 13 percent of these cases. Previously, there were no targeted therapies available to treat this kind of mutation. Many researchers thought it could never be treated.

On May 28, 2021, the U.S. Food and Drug Administration approved the first KRAS inhibitor, sotorasib (Lumakras). This medication targets only the mutated form of KRAS and leaves the healthy form of the enzyme alone.

RET

RET is another RTK that is rarely mutated in NSCLC. Two targeted therapies, pralsetinib (Gavreto) and selpercatinib (Retevmo), have been developed to block the receptor from sending growth signals.

Shutting Down Supply Lines

Another class of targeted therapies used to treat NSCLC is angiogenesis inhibitors. These drugs stop new blood vessels from forming around tumors.

A blood supply provides tumors with the oxygen and nutrients they need to grow. Tumors create their own new blood vessels in a process known as angiogenesis. Vascular endothelial growth factor (VEGF) tells cells to create these new blood vessels.

Targeted therapies were developed to stop this process. Ramucirumab (Cyramza) and bevacizumab (Avastin) are monoclonal antibodies that bind to VEGF itself and stop it from interacting with its receptor. This limits the tumors’ blood supply and shrinks them.

Side Effects of Targeted Therapies

As with any medication, targeted therapies come with some side effects. Many TKIs have similar side effects because the drugs are designed to work the same way and block similar receptors.

Common side effects of targeted therapies used in lung cancer include:

  • Skin problems
  • Dry mouth
  • Dizziness
  • Issues with wound healing
  • Fatigue
  • Vision problems
  • Mouth sores
  • Loss of appetite
  • Constipation
  • Diarrhea
  • Infusion reactions from injected therapies
  • Changes in blood sugar levels
  • Joint pain
  • Hair loss

Many of these side effects overlap with other types of cancer treatment, including chemotherapy, radiation therapy, and immunotherapy. If you are undergoing several types of treatment at once, it may be hard to pinpoint which treatment is causing which side effect.

Talk With Others Who Understand

MyLungCancerTeam is the social network for people with lung cancer and their loved ones. On MyLungCancerTeam, more than 5,800 members come together to ask questions, give advice, and share their stories with others who understand life with lung cancer.

Have you used targeted therapy to treat your lung cancer? Share your experience in the comments below, or start a conversation by posting on your Activities page.

All updates must be accompanied by text or a picture.
Richard LoCicero, M.D. has a private practice specializing in hematology and medical oncology at the Longstreet Clinic Cancer Center, in Gainesville, Georgia. Review provided by VeriMed Healthcare Network. Learn more about him here.
Emily Wagner, M.S. holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology. Learn more about her here.

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