Posted: Tuesday, May 3, 2022
Chendi Li, PhD, of Massachusetts General Hospital, Charlestown, and colleagues reported that the loss of tumor suppressor serine/threonine kinase 11/liver kinase B1 (STK11/LKB1) may be associated with increased sensitivity to combined mitogen-activated protein kinase (MAPK) and myeloid cell leukemia 1 (MCL1) inhibition with the novel MCL1 inhibitor AMG 176 in patients with KRAS-mutant non–small cell lung cancer (NSCLC). These preclinical research findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 2150).
“These results reveal a novel link between LKB1 and the regulation of BCL2 family proteins,” said the authors. “[They] provide [a] preclinical rationale for evaluation of combined KRAS G12C + MCL1 inhibitors for KRAS-LKB1–mutant NSCLC.”
The study screened a panel of KRAS-mutant NSCLC cell lines as well as patient-derived xenograft mouse models. The study analyzed the KRAS G12C inhibitor sotorasib (AMG 510) in the treatment of these patients.
Restoration of LKB1 expression in LKB1-deficient cell lines and patient-derived xenograft tumors weakened the apoptotic response to MAPK plus MCL1 inhibition. Alternatively, deletion of LKB1 in LKB1 wild-type models increased sensitivity to this combination strategy. Mitochondrial apoptotic cell death was regulated by interactions between pro- and antiapoptotic BCL2 family members. Additionally, LKB1-deficient cells exhibited increased association of MCL1 upon MAPK inhibition, effectively priming cells for death upon inhibition of MCL1, according to the authors.
Mechanistically, LKB1 deficiency and associated loss of NUAK phosphorylation appears to lead to hyperactivation of the JNK phosphokinase network. JNK phosphorylates MCL1 at S64 and T163, which reportedly enhances MCL1 protein-protein interaction. This series of phosphorylation events increased the dependence of MCL1 and seemed to make KRAS-LKB1–mutant tumors more vulnerable to MAPK plus MCL1 inhibition. Consistent with this mechanism, a patient with KRAS-LKB1 mutant NSCLC received ex vivo treatment with sotorasib or trametinib, which increased MCL1-dependent priming.
Disclosure: For full disclosures of the study authors, visit www.abstractsonline.com.