Concomitant BRAF and PI3K/mTOR Blockade Is Required for Effective Treatment of BRAFV600E Colorectal Cancer

Abstract

Purpose BRAFV600E mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Whereas selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAFV600E CRC. Experimental Design We examined phosphatidyl inositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling in BRAFV600E CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAFV600E CRC. Results Western blot revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAFV600E GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression. Conclusions We have established a novel GEMM to interrogate BRAFV600E CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials.

Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models

“…Intrinsic resistance appears to derive from upregulation of EGFR activity in response to BRAF inhibition, resulting in sustained activation of the AKT pathway (42;43). Combined treatment with BRAF and EGFR or PI3K/mTOR inhibitors has a synergistic effect and is being tested as a therapeutic strategy for BRAF mutant colorectal cancers in the clinic (42-44). HSP90 inhibition offers an alternative method of targeting upregulated EGFR and achieving simultaneous inhibition of the MAPK and AKT pathways, suggesting an HSP90/BRAF inhibitor combination could also be an effective approach in BRAF mutant colorectal cancer.…”

B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells

“…Taken together, our study highlights the possibility for a novel therapeutic rationale for using B-Raf/MEK/ERK pathway inhibitors in colorectal carcinoma and potentially other carcinoma entities. Thus, these drugs could potentially limit metastasis, most likely, in combination with conventional chemotherapy or other targeted therapy compounds such as EGFR or dual PI3K/mTOR inhibitors (4,(17)(18)(19)(20). Such combinations, which target various hallmarks of cancer, are currently in clinical trials for colorectal carcinoma.…”

“…Nevertheless, these inhibitors still elicited partial responses and stabilized disease in some patients (14,15). Depending on their mutational landscape, BRAF-mutant colorectal carcinoma cell lines display differential sensitivity toward B-Raf or MEK inhibitors in tissue culture and xenograft models (4,13,(16)(17)(18). Thus, these compounds still hold clinical promise, in particular if their combination with other substances is considered and once the complex pathology and genetic heterogeneity of colorectal carcinoma are better understood.…”

Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies

“…The reason for this differential outcome is a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF (V600E) inhibition [83,84]. Therefore, combination strategies of BRAF plus EGFR inhibition or other pathway interacting approaches (cotargeting BRAF plus MEK or PI3K) are required [85][86][87] (Table 2). Apart from novel target therapy approaches, the FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant fit (!)…”