Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

Abstract

Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor-β (TGFβ) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGFβ-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

“…Many theories have been proposed to explain resistance and researchers are tirelessly seeking strategies to overcome it. Using a whole-genome synthetic lethal RNA interference screen, Marini et al identified that the Activin pathway is essential for platinum resistance [ 107 ]. Blocking activin and growth differentiating factor 11 can significantly improve platinum induced cancer cell death.…”

Dynamic analysis of pulsed cisplatin identifies effectors of resistance in lung adenocarcinoma

“…In order to directly compare the response of lung adenocarcinoma cells to the continuous presence of cisplatin, or a pulse of cisplatin that mimics in vivo pharmacokinetics (2h, 5 μg/mL) ( Figure 1A), we monitored the growth and apoptosis of the innately resistant A549 lung adenocarcinoma cell line (Marini et al, 2018) by live cell imaging under both conditions ( Figure 1B). This analysis demonstrated that while continuous exposure to cisplatin resulted in decreased cell number and increased apoptosis over 72h, a pulse of cisplatin only reduced the rate of cell proliferation and did not induce apoptosis.…”

“…To further examine the differences between these two models, we used multiplexed, bead-based protein analysis to investigate the DNA damage, apoptotic and signalling response for key pathway components previously implicated in the response to continuous cisplatin exposure (I.e. p38, ERK, JNK and MCL-1) (Marini et al, 2018, Stewart, 2007 (Figure 1C, Supplementary Figure 1). As might be expected, the continuous exposure model resulted in a significantly elevated and sustained DNA damage response when compared to the pulse model, particularly for the phosphorylation of Chk2 (Ser345), p53 (Ser15 and Ser46), pH2A.X (Ser139 -γH2A.X) and expression of p21 and MDM2.…”

“…To gain an understanding of the wider signalling networks associated with resistance to platinum therapy, we utilised multiplexed, magnetic bead based assays to profile the signalling and DNA damage response at multiple time points following a 2 h pulse of cisplatin, across all six cell lines ( Figure 1F). For this analysis, we tracked the dynamics of 47 different protein analytes ( Supplementary Table 2) over a 72 hour period, focusing on elements of signalling network structures that we recently implicated in platinum chemoresistance (Marini et al, 2018), including the MAPK, PI3K/mTOR, NF-κB and TGFβ pathways, as well as a number of key apoptotic mediators and DNA damage response proteins ( Figure 1G).…”

“…All lung adenocarcinoma cell lines have been previously described (Marini et al, 2018). The lines were cultured in Advanced RPMI (serial no) containing 1% FCS and 1% GlutaMAX (serial no) under standard tissue culture conditions (5% CO2, 20% O2).…”