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. 2021 Mar 2;26(4):e530–e536. doi: 10.1002/onco.13702

Figure 2.

Figure 2

Noncanonical and canonical ER signaling axis. We hypothesized that the partial agonist activity of tamoxifen versus the estrogen depletion effect of letrozole might explain the observed and widely different clinical responses [13, 14, 15, 16]. We also hypothesized that noncanonical ER signaling might be involved, in which MER can drive noncanonical ER signaling [13, 15, 23]. We constructed a map of the signaling pathway that comprises the described interactions, and we considered each of the treatment scenarios and responses. We found that our hypothesized mechanisms could potentially explain the diverging responses to tamoxifen and letrozole when combined with trametinib in a patient with hyperactivated RAS pathway signaling. (Scenario 1): MER‐driven noncanonical ER signaling and RAS signaling (replicating baseline condition of current case report). MER/E2 activates AKT and ER, which leads to cell growth. Activation of EGFR subsequently activates RAS/MAPK pathway, which also leads to growth signaling (similar to KRAS mutation). (Scenario 2): TMX functions as a partial agonist for MER‐driven noncanonical ER signaling. Thus, no inhibitory effect is seen on ER signaling. (Scenario 3): Combination treatment with tamoxifen and trametinib is not sufficient to halt the cell growth despite the successful inhibition of RAS/MEK pathway with trametinib because ER signaling is not adequately reduced with tamoxifen. (Scenario 4): Combination of estrogen depletion (mimicking treatment with letrozole) and trametinib successfully inhibits both ER and RAS signaling, thus leading to the inhibition of cell growth. (Scenario 5): Combination of estrogen depletion (mimicking treatment with letrozole) and erlotinib (EGFR inhibitor to reduce RAS activation) successfully reduces both ER and RAS signaling, thus leading to the inhibition of cell growth. Abbreviations: E2, estradiol; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; MAPK, mitogen‐activated protein kinase; MEKi, MEK inhibitor; MER, membrane estrogen receptor; pAKT, phospho‐AKT; pER, phospho‐ER; TMX, tamoxifen.