Celebrating the 10th Anniversary

A decade of discoveries in Cancer Discovery. For the community. By the Community.

Authors

Their impactful studies. In their words.

Our proof-of-concept study published in Cancer Discovery changed the treatment choice for BRAF-mutant colorectal cancer.

EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
March 2012

Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF^V600E-Mutant Colorectal Cancer
April 2018

Q: What unanswered questions in the field were these studies addressing?

A: (Ryan B. Corcoran) These studies explored the mechanism underlying lack of response to BRAF inhibitors in BRAF^V600E colorectal cancer. While BRAF inhibitors produced response rates of >50% in BRAF^V600E melanoma, they yielded only a ∼5% response rate in BRAF^V600E colorectal cancer, which remains one of the most striking examples to date of tumor type–specific response to targeted therapy. At the time, the prevailing hypothesis to explain this differential sensitivity was that colorectal cancer was simply not as dependent on BRAF signaling as melanoma and that other signals independent of the BRAF pathway were able to maintain survival in the presence of BRAF inhibitors. These studies aimed to test whether this hypothesis was true or whether an alternative mechanism might underlie the lack of response in colorectal cancer that could be exploited to improve clinical benefit in patients with BRAF^V600E colorectal cancer.

Q: What surprised or excited you most about the findings?

A: (Jeffrey A. Engelman) The mechanism was clear and logical and there were immediate clinical implications that could impact patient care.

A: (Hiromichi Ebi) It had been believed that a driver oncogene played similar roles among various tumor types. This informed the development of protein-specific targeted therapies, predicted to inhibit tumor growth in a genotype-specific manner regardless of tumor origins. On the contrary, our finding indicated that the presence of EGFR in colorectal cancer caused a tissue-specific feedback in colorectal cancer that was absent in melanoma. While the elucidated mechanisms turned out to be simple, the most exciting thing was the translational impact of our findings because anti-EGFR antibody was already approved for the treatment of colorectal cancer.

Q: What has been the paper’s greatest impact in the years that followed?

A: (Hiromichi Ebi) Our proof-of-concept study published in Cancer Discovery changed the treatment choice for BRAF-mutant colorectal cancer.

A: (Ryan B. Corcoran) The finding that EGFR can drive adaptive feedback reactivation of MAPK signaling following BRAF inhibition in BRAF^V600E colorectal cancer led to a series of clinical trials that culminated in the first FDA approval for BRAF^V600E colorectal cancer in 2020, of a BRAF inhibitor in combination with an EGFR antibody. More broadly, these studies helped to establish the concept of adaptive resistance and the importance of feedback pathway reactivation in driving resistance to inhibitors of the RAS–RAF–MAPK, particularly in tumors such as colorectal cancer. These same fundamental mechanisms have proven important with other clinical inhibitors of this pathway, including the new class of mutant-selective KRAS^G12C inhibitors that have entered the clinic and are currently helping to guide the first wave of KRAS^G12C inhibitor combination clinical trials.