Therapeutic targeting of BRAF fusion altered lung cancer

2022

Career Development Award

Michael Offin, MD

Memorial Sloan Kettering Cancer Center

New York

Alterations in the BRAF gene can lead to the development of non-small cell lung cancer. BRAF fusions are a type of BRAF gene alterations. These fusions are powerful growth stimulators of lung cancer. Currently, no treatment exists for cancers that harbor these BRAF fusions. Dr. Offin will be testing a series of new drugs in preclinical cell line and animal models of lung cancer. The ultimate goal of his project is to identify new drugs that can be tested in clinical trials.

Research Summary

With the growing adoption of next-generation sequencing (NGS) as a standard of care diagnostic test for patients with lung cancers we have an increased understanding of the genetic landscape of these tumors and strive to derive novel targeted treatment options. BRAF is a protein member of the RAF family kinases and is part of a signaling cascade that, when activated, can lead to cell growth. Under normal physiological conditions the activity of RAF kinases is tightly controlled by negative regulators and down-regulation of growth factor action to prevent uncontrolled cell growth and tumor formation. In cancers, BRAF can be permanently activated by genetic events when alterations occur in the active part (kinase domain) of the enzyme or when the kinase domain is fused with parts of other proteins leading to uncontrolled activation of BRAF. There is currently no approved or recommended therapy for cancers that arise from BRAF fusions. Our goal in this proposal is to test three small molecule inhibitors that target BRAF fusions in disease models derived from patient tissue (patient-derived xenografts [PDX]) to determine the most effective drug that can move forward to a phase 1 clinical trial. We also aim to generate additional tractable patient-derived models that will aid in exploring and developing new therapy for people with cancers driven by BRAF fusions. Finally, in order to develop combinatorial therapy, we aim to identify the signaling pathways active in patient-derived and isogenic cell lines engineered to express BRAF fusions. The applicant is ideally situated to translate these findings to the clinic.

Technical Abstract

Rearrangement of the BRAF gene results in a potent oncogene that is a driver in 2.8% of NSCLC with BRAF alterations. To date there is no approve targeted therapy for any cancer type with BRAF fusions. Studies by our group and others have shown that mutant-specific BRAF kinase inhibitors do no inhibit BRAF fusion kinases. Instead, pan-RAF inhibitors seem more effective as therapy for cancer cells harboring these fusions. We therefore hypothesize that targeting BRAF fusions with pan-RAF inhibitors are likely to be effective therapy for this molecularly defined subset of NSCLC. Our goal in this proposal is to generate the preclinical data necessary to propel a phase 1 clinical trial of a pan-RAF inhibitor specific to patients with NSCLC harboring a BRAF fusion. We have generated seven preclinical disease models with BRAF rearrangement, including two NSLC patient-derived xenograft models with matching cell lines that will allow this project to go forward immediately. In Aim 1 we propose to generate additional NSCLC PDX, organoid and cell line models that will expand the platforms available to examine the efficacy of these BRAF inhibitors. We will test the efficacy of three pan-RAF inhibitors (LY3009120, belvarafenib, KIN-2787) in vitro and in vivo in Aim 2. We believe that combination therapy may eventually be necessary to extend the duration of response to BRAF targeted therapy. To find candidates that can be exploited for combination therapy, in Aim 3 we will map the signaling pathways that are activated by BRAF fusions in isogenic cell lines and inhibited specifically by BRAF inhibitors in cells with BRAF fusions. Given that resistance to therapy is inevitable, we will seek to generate resistance to the three pan-RAF inhibitors in vitro and in vivo and then identify and validate potential mechanisms of resistance. To be able to bring the goals of this proposal to fruition, I have assembled a team with clinical, translational and basic research expertise to help guide me. As a thoracic oncologist with clinical trial expertise, I am ideally situated to translate the findings of this study to the clinic.

Key words

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

Targeted therapy

Therapeutic targeting of BRAF fusion altered lung cancer

LUNGevity Foundation

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