<i>EGFR</i>-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [<i>MET</i>] gene amplification, Kirsten Rat Sarcoma [<i>KRAS</i>], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [<i>PI3KCA</i>], and RAF murine sarcoma viral oncogene homolog B1 [<i>BRAF</i>] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies.
This review not only focuses on important and readily identifiable subsets, including primary tumor side and v-RAF murine sarcoma viral oncogene homologue B (BRAF) mutations, but also discusses rarer molecular subgroups that may be important for determining treatment in the future.
Small kinase inhibitors of v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) have shown considerable antineoplastic activity in some tumor types harboring activating BRAF-V600 mutations (e.g., melanoma) and promising data are emerging on BRAF inhibitor therapy of mutation-bearing primary brain tumors.
The mitogen-activated protein kinase kinase 1 and 2 signaling pathway is a major component of the RAS (Rat sarcoma)/RAF (Radpidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERKs (Extracellular signal-regulated kinases) signaling axis that regulates tumorigenesis and cancer cell growth.
Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers.
In order to determine whether 5' truncation alone could activate cellular raf, we constructed 21 human c-raf-1 cDNAs with variable BAL 31-generated deletions distal to a Moloney murine sarcoma virus long terminal repeat and a consensus translation initiation sequence.