Role of MEK inhibition in improving anti-tumor responses in xenograft models of BRAF-mutated metastatic colorectal cancer.

Abstract

265 Background: BRAFV600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (mCRC) and are associated with poor survival outcomes. Addition of anti-EGFR therapy improves responses when combined with BRAF inhibition, yet acquired resistance to targeted therapies invariably develops. Novel therapeutic approaches to deepen anti-tumor activity are warranted for patients with this subset of mCRC. Methods: Patient-derived xenograft (PDX) models of BRAFV600E mCRC were established and treated with vemurafenib (V) +/- cetuximab (C) until acquired resistance. DNA from resistant tumors was sequenced and compared to that of untreated controls. BRAFV600E mCRC tumors from PDX mice with acquired mutations in MAPK signaling were reimplanted into another generation of nude mice and treated with V +C or trametinib (T) + cetuximab. Results: Twelve resistant models were developed in BRAFV600E mCRC PDX models treated with V +/- C, with nine models demonstrating acquired mutations resulting in MAPK pathway re-activation, including codons 12 or 13 KRAS mutations. While sensitivity to V + C was observed in BRAFV600E /KRASwild-type mCRC tumors, this combination demonstrated no anti-tumor response in BRAFV600E models with acquired KRASG12R or KRASG12D mutations. In these PDX models harboring dual BRAF/KRAS mutations, the combination of T + C generated sustained tumor regression not observed with V+C (P <.001 for both BRAFV600E / KRASG12R and BRAFV600E /KRASG12D models). Addition of T following resistance to V+C restored sensitivity in both models. Conclusions: Dual blockade of BRAF + EGFR has shown promise in early-phase clinical trials for patients with BRAFV600E mCRC, and MAPK pathway reactivation appears to be a critical mechanism of resistance. These results suggest that use of a MEK inhibition may reverse such acquired resistance. While MEK + EGFR targeting has been associated with excessive skin toxicity in humans, these data provide rationale for the pursuit of triple BRAF + MEK + EGFR inhibition in patients with BRAFV600E mCRC.