Genetic Mutations Linked to Lung Cancer: TP53, KRAS, EGFR, ALK, and Others Explored

Genetic Alterations in Lung Cancer: Insights into TP53, KRAS, EGFR, ALK, and Other Variants

Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer, and understanding the role of gene mutations in its development can help in the selection of effective treatments.

Genes provide instructions for how the body functions and control cell growth and division. In NSCLC, certain gene mutations can prevent DNA repair, cause cells to grow uncontrollably, or make cells live longer. These extra cells can form tumors, leading to cancer.

One such mutation is the ALK gene, found in approximately 5-7% of NSCLC cases. This mutation is common in younger people and nonsmokers. Alectinib (Alecensa), brigatinib (Alunbrig), ceritinib (Zykadia), crizotinib (Xalkori), lorlatinib (Lorbrena) are drugs that target ALK gene mutations.

Another significant mutation is the MET gene, which is changed in about 30% of all NSCLCs. MET-positive lung cancers tend to be more aggressive than lung cancers without the mutation. Capmatinib (Tabrecta) and tepotinib (Tepmetko) are treatments for the METex14 mutation.

EGFR-positive cancers account for around 10% to 15% of all lung cancers in the United States and are more common in women and nonsmokers. EGFR inhibitors block signals from the EGFR protein and treat EGFR mutations. Osimertinib (Tagrisso) is the only drug currently available to treat the EGFR exon 19 deletion, EGFR exon 21 L858R point, and EGFR exon T790M mutations.

The TP53 gene mutation is found in 40% to 51% of all NSCLC cases and is usually acquired, happening in both smokers and non-smokers. Research suggests that TP53 mutations combined with EGFR, ALK, or ROS1 mutations are linked to a shorter survival time for people with NSCLC.

Between 1% and 4% of NSCLCs involve the human epidermal growth factor receptor 2 gene mutation (HER2). It's most common in people with adenocarcinomas and people who have never smoked. Fam-trastuzumab deruxtecan-nxki (Enhertu) is the first targeted therapy for people with the HER2 mutation.

The KRAS mutation is found in about 30% of all NSCLCs and is more common in people who smoke. The outlook for people with this type of mutation is less favorable than for people who don't have it. Sotorasib (Lumakras) is the first KRAS inhibitor approved by the FDA for lung cancer.

Some of the less common mutations linked to NSCLC include NRAS, neurotrophic tyrosine receptor kinase (NTRK), RET, ROS1, and each of these affects less than 2% of NSCLC cases. Entrectinib (Rozlytrek) and larotrectinib (Vitrakvi) are drugs available to treat cancers caused by the NTRK mutation. Pralsetinib (Gavreto) and selpercatinib (Retevmo) are RET inhibitors. Ceritinib (Zykadia), crizotinib (Xalkori), entrectinib (Rozlytrek), and lorlatinib (Lorbrena) are RET inhibitors that treat ROS1-positive lung cancers.

The results of genetic tests for NSCLC can take 1 to 2 weeks. Today, a number of treatments target specific gene mutations in NSCLC. Your doctor should test your tumor when you're diagnosed and let you know if you're a good candidate for a targeted drug. In some cases, you may also qualify for a clinical trial. Off-label drug use means a drug that's approved by the FDA for one purpose is used for a different purpose that hasn't yet been approved. Doctors can still prescribe drugs however they think is best for their patients.

The PIK3CA gene mutation was found in 6% of lung cancer samples in a 2024 study and is more common in squamous cell lung carcinomas than in adenocarcinomas. Dabrafenib (Tafinlar) and trametinib (Mekinist) are drugs that target BRAF V600E mutations. Up to 3.5% to 4% of NSCLCs test positive for BRAF mutations, with most cases being current or former smokers.

In conclusion, understanding the role of gene mutations in NSCLC is crucial for the selection of effective treatments. A number of targeted therapies are available, and more are being developed. It's essential to discuss treatment options with your doctor to determine the best course of action for your individual case.