Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Abstract

Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

Vasculogenic mimicry in small cell lung cancer

“…CDX3 tumours were dissociated to single cells with Miltenyi Biotecs tumour dissociation kit according to manufacturer's recommendations on a gentleMACS dissociator52. Single cells underwent immunomagnetic depletion of mouse cells and dead cells with a Dead cell removal microbead set (Mitenyi Biotec), anti-mouse anti-MHC1 antibody (eBioscience clone, 34-1-2s) and anti-mouse anti-IgG2a+b microbeads over a LS column in a MidiMACS Seperator (Miltenyi Biotec).…”

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…In small cell lung cancer (SCLC), ABT-737, navitoclax and venetoclax have shown antitumor activity in cell lines and xenograft models (44, 133–136) and limited single-agent activity has been observed with navitoclax in patients with SCLC (137, 138). Combination with other chemotherapeutic agents including rapamycin and vorinostat, or inhibition of other signaling pathways such as PI3K/BMX, appears to be a promising approach to overcoming resistance and enhancing sensitivity to BH3 mimetics in SCLC (139–142). …”

Targeting Apoptosis Signalling in Cancer: How Decreasing BAK Phosphorylation via BMX Inhibition Increases Sensitivity to Cytotoxic Drugs

“…Investigation of the effects of combination of a dual PI3K/mTOR inhibitor which modulated BMX activity with the pro-apoptotic BH3 mimetic ABT737, revealed an increase in cellular sensitivity with the combination compared to either agent alone. As shown in (Figure 1) and outlined above PI3K is one of the upstream regulators of BMX, and interestingly it was found that it was the effect of PI3K inhibition on BMX activity rather than on AKT or mTOR that was responsible for the increased sensitivity observed both in colorectal cancer cell models [9] and small cell lung cancer [10]. Together with our mechanistic study these findings suggest strongly that when it comes to BMX inhibition, either directly [6] or via modulating upstream regulators such as PI3K [9,10], a combinatorial approach would be most effective.…”

“…As shown in (Figure 1) and outlined above PI3K is one of the upstream regulators of BMX, and interestingly it was found that it was the effect of PI3K inhibition on BMX activity rather than on AKT or mTOR that was responsible for the increased sensitivity observed both in colorectal cancer cell models [9] and small cell lung cancer [10]. Together with our mechanistic study these findings suggest strongly that when it comes to BMX inhibition, either directly [6] or via modulating upstream regulators such as PI3K [9,10], a combinatorial approach would be most effective. However, it remains to be established whether upstream PI3K inhibition is able to modulate BMX activity with enough amplitude and duration to be effective or whether directly targeting BMX may be a better approach.…”