Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations

Abstract

Liver kinase B1 (LKB1/STK11) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerabilities of this subgroup of tumors exploitable to design specific therapies we screened an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1. Among eight hit compounds, Birinapant, an inhibitor of the Inhibitor of Apoptosis Proteins (IAPs), was the most active compound in LKB1-deleted clone only compared to its LKB1 WT counterpart. We validated the Birinapant cells response and its mechanism of action to be dependent on LKB1 deletion. Indeed, we demonstrated the ability of this compound to induce apoptosis, through activation of caspases in the LKB1-deleted clone only. Expanding our results, we found that the presence of KRAS mutations could mediate Birinapant resistance in a panel of NSCLC cell lines. The combination of Birinapant with Ralimetinib, inhibitor of p38a, restores the sensitivity of LKB1-and KRAS-mutated cell lines to the IAP inhibitor Birinapant. Our study shows how the use of Birinapant could be a viable therapeutic option for patients with LKB1-mutated NSCLCs. In addition, combination of Birinapant and a KRAS pathway inhibitor, as Ralimetinib, could be useful for patients with LKB1 and KRAS-mutated NSCLC.

miR-17 Epigenetic Modulation of LKB1 Expression in Tumor Cells Uncovers a New Group of Patients With Poor-Prognosis NSCLC

“…[1][2][3][4] Furthermore, we reported that the introduction of KRASmutant isoforms in H1299 cell line triggered a metabolic reprogramming different from that observed in the KRAS WT cell line, 5 which in turn differently influenced cell metabolic responses to treatments 6 and nutrient addiction. 7 In most of the manuscripts cited previously and in other contexts, 8,9 we also reported that KRAS-mutant clones derived from H1299 cell line had similar features of the endogenously mutated KRAS NSCLC cell lines.…”

A technical note on emerging combination approach involved in the onconanotherapeutics

“…Colombo et al have evaluated the anticancer effect of birinapant (apoptosis inhibitor) and ralimetinib (p38 inhibitor) in the liver kinase B1 deleted clone and RAS muted cell lines and the outcome showed restoration of kinase activity (Colombo et al, 2020 ). In another study by Mortensen et al, the combination of onalespib and cisplatin significantly increased the antiproliferative, pro apoptotic, and antimigratory effect (Mortensen et al, 2020 ).…”

Cellular heterogeneity in TNF/TNFR1 signalling: live cell imaging of cell fate decisions in single cells

“…Whilst this approach has been employed extensively to investigate TNF-induced inflammation [ 18 , 23 , 31 – 33 ], and to some extent TNF-induced cell death [ 34 – 36 ], the role of TNF/TNFR1 signalling pathway crosstalk in guiding cell-fate decisions in single cells has been understudied. It is vital to understand the mechanisms driving cell-to-cell variability in response to TNF and modulators of the TNF/TNFR1 signalling pathway, as drugs designed to promote TNF-induced cell death suffer from fractional killing [ 37 – 40 ], and poor responses in various cell lines [ 39 , 41 ].…”