Selective Targeting of BRAF and KRAS Mutant Tumors: The Promise of QLH11906 Pan-RAF Inhibitor

The study focuses on the development of a new type of RAF inhibitor, QLH11906, designed to overcome limitations associated with existing BRAF inhibitors like vemurafenib. These inhibitors have been effective for melanoma patients with BRAF V600E mutations but have seen limited use due to side effects like itching and skin papilloma, which are linked to the activation of the MAPK pathway. The paradoxical activation of this pathway also promotes tumor growth in melanoma with wild-type BRAF and causes skin toxicity in patients with KRAS mutations.

To address this, researchers tested QLH11906 on various RAF kinases and a range of other kinases to ensure its selectivity. The drug was found to inhibit wild-type A/B/C RAF and the BRAF V600E mutation with high potency and did not affect other tested kinases at a concentration of 1 μM, except for DDR1 and DDR2.

In 2D culture, QLH11906 effectively reduced the proliferation of cell lines with BRAF and KRAS mutations and decreased ERK phosphorylation. The drug showed enhanced activity in 3D cultures, particularly in cell lines HCT116 and Calu-6. Immunoprecipitation studies revealed that QLH11906 could disrupt both BRAF homodimers and BRAF/CRAF heterodimers.

Combination studies with MEK inhibitors demonstrated a synergistic effect in KRAS-mutant cell lines, leading to a significant reduction in tumor growth. This effect was also observed in patient-derived organoid models of various cancers.

In vivo studies showed that QLH11906 could induce tumor shrinkage as a single agent in certain cell line-derived xenograft models and in combination with trametinib in patient-derived xenograft models of lung and colon cancers.

The findings suggest that QLH11906 is a potent and selective pan-RAF inhibitor with significant antitumor activity in both cell culture and animal models. It holds promise as a potential therapeutic for patients with BRAF and KRAS-mutant tumors.