Combined inhibition of KRAS and mTORC1 kinase is synergistic in non-small cell lung cancer.

Current KRAS (OFF) inhibitors that target inactive GDP-bound KRAS cause responses in less than half of patients and these responses are not durable. A class of RAS (ON) inhibitors that targets active GTP-bound KRAS blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity.

EGFR Blockade Reverts Resistance to KRAS Inhibition in Colorectal Cancer.

Most patients with -mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS inhibitors in colorectal cancer, we examined the effects of AMG510 in colorectal cancer cell lines. Unlike NSCLC cell lines, colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation.

Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema.

Background: Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration.