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Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway.

Chen Y, Huang R, Ding J, Ji D, Song B, Yuan L, Chang H, Chen G - Sci Rep (2015)

Bottom Line: The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor.Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells.Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

View Article: PubMed Central - PubMed

Affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.

ABSTRACT
Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

No MeSH data available.


Related in: MedlinePlus

Afatinib conferred synergistic inhibition with 6AN via inhibition of EGFR pathway.A) Genetic silencing of ERBB2, EGFR, and mTOR respectively in NRAS WT myeloma cells showing no effect of mTOR inhibition in combination treatment; B) Blockade of ERBB2 in myeloma cells did not change downstream effector of mTOR but solely downstream of EGFR; C) Pharmaceutical inhibition of mTOR using rapamycin did not show synergy with 6AN as compared with Gefitinib and Afatinib; D) Scheme of how triple WT MM cells respond to EGFR inhibition and metabolic shift in response.
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f6: Afatinib conferred synergistic inhibition with 6AN via inhibition of EGFR pathway.A) Genetic silencing of ERBB2, EGFR, and mTOR respectively in NRAS WT myeloma cells showing no effect of mTOR inhibition in combination treatment; B) Blockade of ERBB2 in myeloma cells did not change downstream effector of mTOR but solely downstream of EGFR; C) Pharmaceutical inhibition of mTOR using rapamycin did not show synergy with 6AN as compared with Gefitinib and Afatinib; D) Scheme of how triple WT MM cells respond to EGFR inhibition and metabolic shift in response.

Mentions: With aforementioned results, we speculate addition of PPP inhibitor in the setting of triple WT cells. Combination of 6AN not only synergistically inhibited the proliferation of triple WT myeloma cells but also decreased the migratory capacity (Fig. 4A–B). Similar effects were also acquired using the EGFR/ERBB2 dual inhibitor Afatinib (Fig. 4C). As it has been reported that 6AN effects with the production of intracellular reactive oxygen species (ROS), which impeded NADPH generation, we supplemented the triple WT cells with NADPH and the inhibition was restored, whereas the effect was not observed in cells with KRAS/BRAF/NRAS mutations (Fig. 4D; Suppl. Fig. 3A–B). To further validate our findings, we found that genetic silencing of G6PD, a key enzyme in PPP reached similar inhibitory effects to 6AN in combination with EGFR inhibitors (Fig. 5A–B). Both EGFR and PI3K/mTOR pathways were critical downstream signalling routes for ERBB2, a target that Afatinib inhibited. We then tended to elucidate via which pathway Afatinib was effecting in the setting of MM. Using genetic silencing of mTOR, ERBB2, and EGFR, we observed that mTOR activity was basically unchanged when ERBB2 was silenced, and the synergistic effect was not recapitulated with the presence of rapamycin (Fig. 6A–C). In summary, we have shown that combination of EGFR and PPP inhibition could synergistically inhibit triple WT MM cells via NADPH depletion. The dual ERBB2/EGFR inhibitor also effected majorly via EGFR pathway in myeloma cells.


Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway.

Chen Y, Huang R, Ding J, Ji D, Song B, Yuan L, Chang H, Chen G - Sci Rep (2015)

Afatinib conferred synergistic inhibition with 6AN via inhibition of EGFR pathway.A) Genetic silencing of ERBB2, EGFR, and mTOR respectively in NRAS WT myeloma cells showing no effect of mTOR inhibition in combination treatment; B) Blockade of ERBB2 in myeloma cells did not change downstream effector of mTOR but solely downstream of EGFR; C) Pharmaceutical inhibition of mTOR using rapamycin did not show synergy with 6AN as compared with Gefitinib and Afatinib; D) Scheme of how triple WT MM cells respond to EGFR inhibition and metabolic shift in response.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403500&req=5

f6: Afatinib conferred synergistic inhibition with 6AN via inhibition of EGFR pathway.A) Genetic silencing of ERBB2, EGFR, and mTOR respectively in NRAS WT myeloma cells showing no effect of mTOR inhibition in combination treatment; B) Blockade of ERBB2 in myeloma cells did not change downstream effector of mTOR but solely downstream of EGFR; C) Pharmaceutical inhibition of mTOR using rapamycin did not show synergy with 6AN as compared with Gefitinib and Afatinib; D) Scheme of how triple WT MM cells respond to EGFR inhibition and metabolic shift in response.
Mentions: With aforementioned results, we speculate addition of PPP inhibitor in the setting of triple WT cells. Combination of 6AN not only synergistically inhibited the proliferation of triple WT myeloma cells but also decreased the migratory capacity (Fig. 4A–B). Similar effects were also acquired using the EGFR/ERBB2 dual inhibitor Afatinib (Fig. 4C). As it has been reported that 6AN effects with the production of intracellular reactive oxygen species (ROS), which impeded NADPH generation, we supplemented the triple WT cells with NADPH and the inhibition was restored, whereas the effect was not observed in cells with KRAS/BRAF/NRAS mutations (Fig. 4D; Suppl. Fig. 3A–B). To further validate our findings, we found that genetic silencing of G6PD, a key enzyme in PPP reached similar inhibitory effects to 6AN in combination with EGFR inhibitors (Fig. 5A–B). Both EGFR and PI3K/mTOR pathways were critical downstream signalling routes for ERBB2, a target that Afatinib inhibited. We then tended to elucidate via which pathway Afatinib was effecting in the setting of MM. Using genetic silencing of mTOR, ERBB2, and EGFR, we observed that mTOR activity was basically unchanged when ERBB2 was silenced, and the synergistic effect was not recapitulated with the presence of rapamycin (Fig. 6A–C). In summary, we have shown that combination of EGFR and PPP inhibition could synergistically inhibit triple WT MM cells via NADPH depletion. The dual ERBB2/EGFR inhibitor also effected majorly via EGFR pathway in myeloma cells.

Bottom Line: The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor.Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells.Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

View Article: PubMed Central - PubMed

Affiliation: Department of Haematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.

ABSTRACT
Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

No MeSH data available.


Related in: MedlinePlus