In this study, Rubinson, Tanaka, and colleagues reveal that a subset of switch-II pocket-binding KRASG12C inhibitors can target all RASG12C proteins. In contrast to KRASG12C-specific compounds, which depend on binding to histidine 95 in the KRAS protein, these pan-RASG12C inhibitors bind within the switch-II pocket in a manner that is independent of position 95, thus allowing binding to HRASG12C and NRASG12C, which harbor distinct amino acids at this position. Furthermore, clinical efficacy of sotorasib plus panitumumab was demonstrated in a patient with NRASG12C-mutant colorectal cancer. Together, these results indicate that pan-RASG12C inhibitors, such as sotorasib, represent a new treatment option for patients with HRASG12C and NRASG12C-mutant cancers.

See article, p. 727.

Somatic alterations that activate JAK2 signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN); however, current clinical JAK inhibitors fail to...

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