2026-08-06T12:05:06Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/267892025-12-18T12:57:24Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Janssen, Kobe author Claes, Filip author Van de Velde, Dido author Wehbi, Vanessa L author Houben, Bert author Lampi, Yulia author Nys, Mieke author Khodaparast, Laleh author Khodaparast, Ladan author Louros, Nikolaos author van der Kant, Rob author Verniers, Joffre author Garcia, Teresa author Ramakers, Meine author Konstantoulea, Katerina author Maragkou, Katerina author Duran-Romaña, Ramon author Musteanu, Mónica author Barbacid, Mariano author Scorneaux, Bernard author Beirnaert, Els author Schymkowitz, Joost author Rousseau, Frederic author 2023-02-28 Mutant KRAS is a major driver of oncogenesis in a multitude of cancers but remains a challenging target for classical small molecule drugs, motivating the exploration of alternative approaches. Here, we show that aggregation-prone regions (APRs) in the primary sequence of the oncoprotein constitute intrinsic vulnerabilities that can be exploited to misfold KRAS into protein aggregates. Conveniently, this propensity that is present in wild-type KRAS is increased in the common oncogenic mutations at positions 12 and 13. We show that synthetic peptides (Pept-ins™) derived from two distinct KRAS APRs could induce the misfolding and subsequent loss of function of oncogenic KRAS, both of recombinantly produced protein in solution, during cell-free translation and in cancer cells. The Pept-ins exerted antiproliferative activity against a range of mutant KRAS cell lines and abrogated tumor growth in a syngeneic lung adenocarcinoma mouse model driven by mutant KRAS G12V. These findings provide proof-of-concept that the intrinsic misfolding propensity of the KRAS oncoprotein can be exploited to cause its functional inactivation. Proc Natl Acad Sci U S A . 2023 Feb 28;120(9):e2214921120. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 36812200 https://hdl.handle.net/20.500.12105/26789 KRAS oncogene peptide protein aggregation protein folding Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein.