Mechanisms of KRAS Inhibitor Resistance Revealed

As the KRAS^G12C inhibitors sotorasib (AMG510; Amgen) and adagrasib (MRTX849; Mirati Therapeutics) move into late-stage clinical testing, researchers have begun to investigate possible mechanisms of acquired resistance to these agents. A recent study revealed that patients with non–small cell lung cancer (NSCLC) or colorectal cancer treated with adagrasib may develop resistance in a variety of ways, including through secondary KRAS mutations, MAPK pathway alterations, genomic rearrangements, or histologic transformation of disease. Results were presented during the first week of the virtual American Association for Cancer Research Annual Meeting 2021, April 10–15.

KRAS^G12C mutations occur in about 13% of NSCLCs and 3% of colorectal cancers, and although sotorasib and adagrasib have shown antitumor activity in these malignancies, “clinical mechanisms of acquired resistance to [KRAS]^G12C inhibitors are unknown,” said presenter Mark Awad, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA. Thus, he and his team set out to characterize resistance mechanisms in patients who stop responding to the therapies.

The study included 30 patients with KRAS^G12C-mutant cancers—23 with NSCLC and seven with colorectal cancer—treated with adagrasib monotherapy. All patients experienced tumor reduction or clinical benefit followed by disease progression. Researchers performed genomic sequencing on pretreatment biopsies and/or circulating tumor DNA samples and compared them with sequenced samples taken at the time of disease progression.

The team identified a single resistance mechanism in seven patients and multiple mechanisms in five. Patients developed a range of secondary KRAS mutations, including G12D, G12R, G12V, G12W, G13D, H95D, H95Q, H95R, R68S, Q61H, and Y96C. Patients also developed other aberrations, including EGFR and MET amplifications; RNAS, BRAF, MAP2K1, and RET mutations; and fusions involving RET, BRAF, RAF1, and FGFR. Two patients lacking genomic resistance mechanisms had histologic transformation from lung adenocarcinoma to lung squamous cell carcinoma.

The development of multiple resistance mechanisms—particularly gene fusions—appeared to be more common in patients with colorectal cancer, although “larger datasets are needed to confirm this observation,” Awad noted. Mutagenesis screens revealed that most KRAS resistance mutations likely result in resistance to multiple KRAS^G12C inhibitors, and thus sequential treatment with such agents may not be beneficial. However, some secondary mutations might offer differential sensitivity.

The findings demonstrate that “diverse mechanisms confer resistance to [KRAS]^G12C inhibitors,” Awad said, and patients may concurrently develop resistance via multiple mechanisms. That some patients simultaneously developed secondary KRAS mutations, downstream BRAF and MEK alterations, and gene fusions is “a bit daunting,” Awad added. “There is intense interest in understanding which combinatorial strategies will be either used at the time of acquired resistance, or moved sooner up front to hopefully delay resistance.” For example, combinations that include downstream inhibitors, such as SHP2, might be effective.

“This is one of the first big cohort analyses on the mechanisms of acquired resistance to the KRAS^G12C inhibitors,” said Kwok-Kin Wong, MD, PhD, of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center in New York, NY, who was not involved in the study. He considers the results exciting, although secondary KRAS mutations and activating mutations in the signal transduction pathway are not necessarily surprising. Histologic transformation, he said, is an unexpected mechanism that merits additional investigation.

For Wong, the study highlights the numerous escape mechanisms that make treating KRAS^G12C-mutant lung cancer with a single agent difficult, pointing to a need for combination strategies.

David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the research either, agreed. “Although the numbers here are relatively small, the results show us that … resistance is complicated and varied,” he said. “Unfortunately, likely there will not be a one-size-fits-all path toward KRAS^G12C resistance.” –Catherine Caruso

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