Treatment of Rare Mutations in Patients with Lung Cancer

Abstract

Lung cancer is a worldwide prevalent malignancy. This disease has a low survival rate due to diagnosis at a late stage challenged by the involvement of metastatic sites. Non-small-cell lung cancer (NSCLC) is presented in 85% of cases. The last decade has experienced substantial advancements in scientific research, leading to a novel targeted therapeutic approach. The newly developed pharmaceutical agents are aimed towards specific mutations, detected in individual patients inflicted by lung cancer. These drugs have longer and improved response rates compared to traditional chemotherapy. Recent studies were able to identify rare mutations found in pulmonary tumors. Among the gene alterations detected were mesenchymal epithelial transition factor (MET), human epidermal growth factor 2 (HER2), B-type Raf kinase (BRAF), c-ROS proto-oncogene (ROS1), rearranged during transfection (RET) and neurotrophic tyrosine kinase (NTRK). Ongoing clinical trials are gaining insight onto possible first and second lines of medical treatment options intended to enable progression-free survival to lung cancer patients.

Recognition of BRAF by CDC37 and Re-Evaluation of the Activation Mechanism for the Class 2 BRAF-L597R Mutant

“…Literature suggests that L597R is an activating mutation (Taha et al , 2021), however, our MEK phosphorylation assays showed that L597R was inactive relative to V600E (Fig 11E). Thus, it appears that dimerization alone of L597R is insufficient, under the conditions used, for the activation of its kinase activity.…”

“…In the case for the class 2 BRAF L597R mutant, CDC37 is unable to complex with already formed dimer of this mutant, which means that elevated levels of BRAF L597R may accumulate in the cytoplasm and enhanced signalling may be established following activation of such a dimer (Fig 12A). In our hands, dimerization of the BRAF L597R mutant was not sufficient to bring about its activation, even though the mutation L597R itself is supposed to be activating (Taha et al ., 2021). We also find that the V600E mutation is unable to activate the BRAF L597R mutant.…”

“…Literature suggests that L597R is an activating mutation (Taha et al, 2021), however, our MEK phosphorylation assays showed that L597R was inactive relative to V600E (Fig 11E).…”

Recognition of BRAF by CDC37 and Re-Evaluation of the Activation Mechanism for the Class 2 BRAF-L597R Mutant

“…Literature suggests that L597R is an activating mutation [ 42 , 43 ]. However, on closer inspection the results suggested this is inferred indirectly by determining cellular levels of phospho-MEK and phospho-ERK [ 44 , 45 ].…”

Editorial: Challenges and opportunities of TKIs in the treatment of NSCLC patients with uncommon mutations

“…Substantial advances have been made in our understanding of the molecular biology of cancer, leading to profound progression in the fields of diagnosis and treatment of non-small cell lung cancer (NSCLC). More recently, many uncommon mutations are gaining attention in NSCLC, including epidermal growth factor receptor exon 20 insertion (EGFR 20ins), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), rearranged during transfection (RET), v-Raf murine sarcoma viral oncogene homolog B (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), and others ( 1 ). Pharmaceutical agents developed to target classical driver mutations detected in NSCLC patients have provided profound and durable responses compared with conventional chemotherapy.…”