Unusual Clinical Experience in _BRAF_ Exon 15 p.K601E-Mutated Lung Cancer: A Case Report and Brief Review of the Literature  
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1 Department of Precision Medicine, University of Campania \"[PERSON]\", 81100 Caserta, Italy; [EMAIL_ADDRESS]  
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2 Division of Oncology, AORN \"Sant\" Anna e San Sebastian\", 81100 Caserta, Italy 2  
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3 Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; [EMAIL_ADDRESS] (P.P. ); [EMAIL_ADDRESS] (F.P. ); [EMAIL_ADDRESS] (C.D.L. ); [EMAIL_ADDRESS] (A.I. ); [PERSON]U.M. ); [PERSON].T.) [PERSON]  
1 Department of Precision Medicine, University of Campania \"[PERSON]\", 81100 Caserta, Italy; [EMAIL_ADDRESS]  
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phenomenon that eventually leads to uncontrolled cell growth and proliferation [3]. Found in 1% to 2% of lung adenocarcinoma, _BRAF_ mutations typically occur in never-smokers, women, and aggressive micropapillary histological types; they also occur in non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, brain tumors, as well as in some inflammatory diseases such as Erdheim-Chester [4; 5]. Alterations in _BRAF_ are highly challenging to target because of their extreme molecular complexity. They are usually classified as p.V600 and p.non-V600 and divided into three classes based on the exon site. Approximately 50% of _BRAF_ mutations in NSCLC patients are p.non-V600 [6]. Class I mutations, namely, mutant p.V600E/K/D/R, occur in the valine residue at amino acid position 600 of exon 15. These mutations lead to a persistent activation of BRAF kinases through the MAPK transduction pathway, thereby presenting high affinity for BRAF and MEK inhibitors [6]. Class II mutation, namely, p.K601, p.L597, p.G464, and p.G469, lie within either the activation segment or the p-loop and signal as RAS-independent dimers [7]. Therefore, such class increase intrinsic kinase activity, blocking the interactions with the P-loop and preserving the auto-inhibited kinase state [7]. Finally, class III mutations are typically found in the p-loop, catalytic loop, or DGF motif and negatively impact BRAF kinase activity. In fact, in contrast to class II, class III non-V600 BRAF mutants have less or no basal kinase activity than wild-type BRAF. Importantly, it has been preclinically demonstrated that these mutants signal as heterodimers with either CRAF or wild-type BRAF in a RAS-dependent dimerization process that leads to upstream activation of MAPK pathway [7]. Since all class II and III BRAF mutations are p.non-V600, they are generally less sensitive to current BRAF inhibitors [7]. Further complexity of _BRAF_ mutations is given by deletions and translocations, being resistant to _BRAF_ and MEK inhibitors. _BRAF_ deletions enhance kinase activity by suppressing the \(\alpha\)C helix in its active conformation, thereby functioning similarly to class I mutants [8]. Moreover, BRAF activating fusions, which are found in less than 1% of NSCLC cases, occur in truncation of the N-terminal CRI auto-inhibitory domain, thereby functioning similarly to class II mutations. By the way, the absence of this domain leads to the constitutive activation of the BRAF pathway [4; 9]. Drug insensitivity to _BRAF_ exon 15 p.K601E-mutant NSCLC has also been reported. This mutation, which belongs to class II mutations, is slightly more frequent, occurring in about 5% of _BRAF_ mutant lung adenocarcinomas. It consists of a single amino acid substitution of lysine with glutamic acid. The fact that its pathway is activated by a BRAF dimer diminishes the binding ability of specific inhibitors, including dabrafenib and verumafenib, and increases the activity of MEK and ERK signals [6]. Poor drug response has also been documented in patients treated with metatinib.