Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer.

Frank Aboubakar Nana,Sebahat Ocak

doi:10.3390/pharmaceutics13091478

Abstract

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the EGFR gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include MET amplification, EGFR C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, PD-L1 and KRAS amplifications and ESR1-AKAP12 and MKRN1-BRAF translocations, as well as BRAF V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of EGFR-mutant NSCLC developing a BRAF V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.

Highlights

Lung cancer is the leading cause of cancer death and the second most commonly diagnosed cancer worldwide [1]
The major clinical obstacle that limits the long-term benefit of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) is the emergence of acquired resistance mechanisms (ARMs) [6,8,28]
The targeted therapy approach may have the advantages of a better safety profile and a better outcome and quality of life than chemotherapy, as reported in first- and second-line settings in EGFR-mutant NSCLC [35,40,41]

Summary

Introduction

Lung cancer is the leading cause of cancer death and the second most commonly diagnosed cancer worldwide [1]. TKIs targeting EGFR activating mutations significantly improved the outcome of EGFR-mutant NSCLC. Pharmaceutics 2021, 13, 1478 intracerebral efficacy in comparison to first-generation EGFR TKIs gefitinib or erlotinib in advanced-stage EGFR-mutant NSCLC [6,7] (Supplementary Table S1). Tumor progression is driven by acquired resistance mechanisms (ARMs) to EGFR TKIs, which are quite heterogenous molecular alterations. The management of EGFR-mutant NSCLC with ARMs to osimertinib presenting multiple targetable alterations is still unclear. Some EGFR-dependent ARMs, such as the EGFR C797S mutation, seem to be targetable with new fourth-generation EGFR TKIs in preclinical studies (e.g., BLU945 [9,10] and EAI045 [11]) and a clinical trial is currently evaluating the efficacy and safety of one of them (BLU-945) in EGFR-mutant NSCLC (Supplementary Table S2). We tackle how we can use EGFR/BRAF/MEK co-inhibition as a new treatment strategy in BRAF activation as an ARM to osimertinib

BRAF-Mutant NSCLC

BRAF Alterations as ARMs to Osimertinib in EGFR-Mutant NSCLC

BRAF V600 Mutation

Non-BRAF V600 Mutations and BRAF Rearrangements

Findings

Discussion and Perspectives