PLX8394 (PLX-8394) is a novel, potent, orally bioavailable and selective inhibitor of the serine/threonine-protein kinase B-raf (BRaf) with anticancer activity. With an approximate 5 nM IC50 for BRAFV600E, it inhibits BRAF. In BRAF-mutant LA models, PLX8394 can avoid the reactivation of the MAPK pathway. Treatment with PLX8394 is successful in vitro and in vivo in BRAFV600E and some non-V600 LA models. Treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance brought on by an alternatively spliced, truncated BRAFV600E that encourages vemurafenib-insensitive MAPK pathway signaling were both successfully treated with PLX8394. A combination therapy that includes PLX8394 and either an EGFR or mTOR inhibitor up front can prevent acquired PLX8394 resistance, which is caused by EGFR-mediated RAS-mTOR signaling. This study offers a biological justification and potential polytherapy plan to support the administration of PLX8394 to patients with lung cancer. By encouraging mitogen-activated protein kinase (MAPK) pathway signaling, oncogenic activation of the protein kinase BRAF promotes tumor growth. BRAF-mutant lung adenocarcinoma (LA) is the most common cause of BRAF-mutant cancer mortality globally because oncogenic mutations in BRAF occur in ~2-7% of LA. However, the spectrum of BRAF mutations in LA includes both BRAFV600E (60% of cases) and non-V600E mutant alleles (~40% of cases), such as BRAFG469A and BRAFG466V. Unlike most tumor types, which primarily harbor the BRAFV600E-mutant allele, LA tumors primarily harbor the BRAFV600E-mutant allele. Clinical trials testing selective BRAF inhibitors, like vemurafenib, in BRAFV600E-mutant patients have been prompted by the presence of BRAFV600E in LA. Despite showing some clinical promise, reactivation of the MAPK pathway signaling frequently leads to both innate and acquired resistance, which limits the long-lasting effects of the available BRAF inhibitors. Furthermore, the ideal therapeutic approach to stop non-V600E BRAF-mutant LA is still unknown.

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