KRAS is one of the most commonly mutated genes in human tumors, including lung, colon and pancreatic cancers. Mutant KRAS has been considered undruggable for decades until the recent development of a new class of covalent inhibitors that are able to inhibit the G12C mutant version of KRAS. This specific mutation is very common in lung cancer patients but also present in colorectal cancer (CRC) patients. KRAS G12C covalent inhibitors, such as AMG510, are currently in early phase clinical trials and show promising results for the treatment of KRAS G12C mutant lung cancer patients. However, KRAS G12C colorectal cancer patients have not shown the same response.
An international team of researchers led by Sandra Misale, research associate at the Sloan Kettering Institute, examined the effects of the experimental cancer drug, AMG510, which targets KRAS G12C cell lines, and found that the efficacy of such KRAS G12C inhibitors is lineage-specific. These findings, published today in Cancer Discovery, a journal of the American Association for Cancer Research, provide a mechanistic understanding of the differences in response to KRAS G12C inhibitor in lung and colorectal cancers. This work identifies a combinatorial approach with improved drug activity that could be tested in patients with colorectal cancer.
“In this work, we sought to understand the mechanisms underlying the lineage difference in non small cell lung cancer and colorectal cancer,” explained Sandra Misale. “Our data indicate that, despite harboring the same mutation, there are intrinsic differences in signaling between the two types of cancer that translate in different sensitivity to KRAS G12C inhibition. These findings have immediate relevance for colorectal cancer patients with tumors bearing KRAS G12C mutations.”
Method and Findings
Misale and colleagues sought to explain the mechanisms of resistance to KRAS G12C inhibitors in colorectal cancer. Using preclinical in vitro models, they showed that, despite the presence of the same KRAS mutation, lung and colorectal cancer cell lines responded to KRAS G12C inhibition in a very different way. Lung cancer cells had a long and robust inhibition while colorectal cancer cells’ growth was impaired only marginally and for a limited amount of time.
They identified the basis for this phenomenon was different levels of KRAS activators in the two tumor types. Receptors on the cell surface, and in particular the epidermal growth factor receptor (EGFR), are proteins involved with physiologic KRAS activation in normal cells. This study showed that, in the colorectal cancer models, this physiological activation mechanism is responsible for the limited response to KRAS G12C inhibition, while lung cancer cells exhibit lower physiologic receptor activation of KRAS and therefore show longer responses in preclinical models and in patients.
By co-targeting EGFR with selective drugs, the researchers showed that colorectal cancer models treated with KRAS G12C inhibitors could now undergo arrest of cell proliferation and cell death. These selective drugs - monoclonal antibodies targeting EGFR - are already approved for the treatment of other subtypes of colorectal cancer.
Finally, the team tested this pharmacological combination in colorectal cancer patient-derived models including 3D models and mice, demonstrating complete tumor regression in these systems.
“EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer” published in Cancer Discovery, a journal of the American Association for Cancer Research, on May 19, 2020. Sandra Misale, research associate at the Sloan Kettering Institute, served as co-corresponding author.