It takes two Exploiting apoptotic priming with BH3 mimetics in colorectal cancer

Colorectal cancer (CRC) is a leading cause of cancer death, and relapse and therapy resistance are driven by cancer stem cells that current treatments fail to eliminate. Most CRCs start with loss of APC, which constitutively activates WNT signaling and drives proliferation. These cells depend heavily on the anti-apoptotic protein BCL-XL, making it an attractive target. However, BH3 mimetics that inhibit BCL-XL cause thrombocytopenia, as platelets also rely on BCL-XL.
This thesis identifies strategies that lower the apoptotic threshold of CRC cells at low, tolerable doses of BCL-XL inhibition. A screen for targets that synergize with the BCL-XL inhibitor A-1155463 identified FGFR4 and we show that BCL-XL inhibition triggers a compensatory response in which FGF2-FGFR4 signaling upregulates MCL-1, revealing that BH3 mimetics actively reprogram survival signaling. We propose and biophysically confirm a direct interaction between FGF2 and the hydrophobic groove of BCL-XL, suggesting broader engagement of BCL-2 family proteins by FGFs. Expanded screening revealed five targets that synergize with BCL-XL inhibition while sparing normal colon organoids and platelets. Among these, combined GSK-3 and BCL-XL inhibition pushes WNT signaling beyond the level CRC cells tolerate, reverts the competitive advantage of Apc-mutant cells, and enables wild-type neighbors to eliminate them through a suppressive secretome, reducing adenoma burden in vivo. Finally, we establish an optogenetic framework to control and visualize apoptosis in living cells to study non-cell-autonomous signaling.
Together, these findings show that BH3 mimetics act on tissues rather than individual cells, and offer safe, tumor-selective strategies for treating and potentially preventing CRC.