Targeting Class II/III Alterations in BRAF Inhibitors

Alison Schram, MD, Memorial Sloan Kettering Cancer Center, New York, NY, gives an overview of her talk on BRAF inhibitors, presented at the 2023 ESMO Targeted Anticancer Therapies Congress.

Dr Schram describes the different classifications of BRAF alterations and how therapeutic strategies should be tailored to the mechanism of pathway activation.

Transcript:

Hi, my name is Ali Schram. I'm from Memorial Sloan Kettering Cancer Center. At the most recent ESMO targeted Anti-Cancer Therapies conference, I discussed BRAF inhibitors targeting class II and III alterations, and I'll tell you a little bit about that today.

As some background, under physiologic conditions, BRAF is activated by upstream RAS and association of BRAF with activated RAS leads to heterodimerization —for example, CRAF:BRAF heterodimers— or homodimerization —for example, BRAF:BRAF homodimers. This pathway is tightly regulated with several levels of negative feedback control that limit physiologic activation of MAP kinase signaling.

BRAF alterations can be grouped into 3 classes on the basis of how they signal. Class I BRAF mutants typified by BRAF V600E signals constitutively activated monomers. They do not require RAS for activation. These mutants strongly activate ERK and feedback suppress upstream signaling.

Non-V600E mutations are sub-classified into class II mutations such as K601, which have intermediate kinase activity and signal as constitutively active RAS-independent dimers that suppress upstream signaling, and class III mutations such as G469E, which have impaired or lack kinase activity and signal as RAS-dependent heterodimers. BRAF fusions and terminal deletions and splice variants typically signal like class II alterations. Class III mutations bind more tightly than wild-type BRAF to RAS and amplify signaling through wild-type RAF and mutant wild-type RAF heterodimers. They often coexist with other upstream mutations in the pathway.

Approved BRAF inhibitors including vemurafenib, dabrafenib, and encorafenib inhibit constitutively active BRAF monomers such as BRAF V600E, but are not effective in class II and class III alterations that signal as dimers. Furthermore, BRAF V600 mutant tumors can develop acquired resistance to these drugs, mediated by BRAF dimerization, effectively converting these mutants to class II alterations.

RAF dimer inhibitors are in development that inhibit both dimer partners and are effective and preclinical models of cancers driven by class II alterations, and to a lesser degree class III alterations. Dimmer breakers are also being studied that block BRAF dimerization. These may be effective in class II alterations.

There are numerous ongoing clinical trials testing dimer inhibitors and breakers alone and in combination with downstream inhibitors including MEK and ERK inhibitors. The majority of these trials are ongoing with limited data presented thus far. Class III alterations may require inhibition upstream that reduces amplified RAS signaling, such as cetuximab, which blocks EGFR for colorectal cancer with BRAF class three alterations.

In summary, BRAF alterations are grouped into 3 classes on the basis of how they activate ERK. Therapeutic strategy should be tailored to the mechanism of pathway activation. Class II and class III mutations remain an unmet need and clinical trials are ongoing testing BRAF dimer inhibitors and dimmer breakers with or without downstream or upstream inhibitors and BRAF non-V600E mutant cancers. Thank you.

Source:

Schram A. BRAF inhibitors: Targeting class II/III alterations. Presented at: 2023 ESMO Targeted Anticancer Therapies Congress; March 6-8, 2023; Paris, France.