Novel therapeutic strategies for targeting kras-driven lung adenocarcinomathe role of inhibitor of differentiation 1

Resumen

KRAS oncogene is the most frequently mutated gene in lung adenocarcinoma (LUAD). However, there are no effective therapies developed for KRAS LUAD patients. This fact highlights the need to identify new molecular targets for this subgroup of patients. It has been demonstrated that genes with a prognostic role in mutant KRAS LUAD patients have previously shown a significantly functional role, yielding potential molecular targets for therapy development. Id1 gene has a relevant role in LUAD, but its implication in the context of KRAS had not been well-defined. The main objective of this work is to determine the clinical, functional and mechanistic role of Id1 in human mutant KRAS LUAD. Here, we have demonstrated that Id1 is an independent prognostic marker in KRAS-mutated LUAD patients and that in vitro Id1 knockdown impairs cell proliferation, induces an arrest in G2/M cell cycle phase and increases apoptosis in LUAD cells harboring KRAS mutations. Moreover, Id1 depletion in KRAS-mutant cells has a negative impact in 1) primary tumor growth, 2) in established tumor maintenance in xenograft models of tumorigenesis and 3) in tumor progression and mice overall survival in a humanized model of cancer colonization to the liver. In summary, Id1 influences cancer cell signaling in KRAS mutations by regulating several protein kinases of the KRAS signaling pathway, in part through the action of FOSL1 transcription factor. On the other hand, our group has carried out a drug repurposing study to reverse the expression of a specific LUAD mutant KRAS gene expression signature. Drug repurposing allows identifying a novel potential drug combination for the treatment of LUAD patients according to a specific genotype that selectively impair cell proliferation in 2D-cultures models both at short-term and long-term exposure, as well as showed a significant negative effect in cell viability in a 3D-culture approach. In addition, the combined therapy is associated with an increase in cell apoptosis only in the context of KRAS-mutant cells and, interestingly, Id1 loss mediates, at least in part, the antitumor response of mutant KRAS LUAD cells to the combined treatment by regulating the expression of the transcription factor cMYC.