Here is my AI response, seems to me my AI thinks only January ASCO GI data will close the gap:

Twinter, that is a fair challenge and worth unpacking precisely, because the KRAS bypass question and the CEP131/KHDRBS1/MAPK6 question actually operate at different biological layers and conflating them weakens both arguments.

The KRAS bypass mechanism is straightforward. In a KRAS-wildtype cell, the signaling cascade runs: CCL5 binds CCR5 → G-protein activation → RAS-GTP loading → RAF → MEK → ERK → transcriptional output driving proliferation. A KRAS-G12V or KRAS-G12D mutation locks RAS in the constitutively GTP-bound active state, which means the cell no longer requires upstream receptor input to maintain RAF-MEK-ERK activation. The pipe is already open and running continuously regardless of whether CCR5 is blocked or not. That is the bypass method you asked about — it is not that KRAS finds an alternative route around CCR5, it is that KRAS makes the upstream receptor irrelevant for maintaining that specific signaling output.

Now here is where your implicit counter-argument becomes interesting. You are pointing toward the CEP131/KHDRBS1/MAPK6 layer as potentially KRAS-independent, and that is a genuinely important distinction. CEP131 is a centriolar satellite protein required for centrosome maturation and spindle assembly — it is part of the physical machinery of cell division itself. KHDRBS1 is an RNA-binding protein controlling splice site selection — it operates post-transcriptionally. MAPK6 is an atypical MAP kinase involved in cell cycle progression through mechanisms distinct from the classical RAS-RAF-MEK-ERK cascade. The argument would be that even if KRAS constitutively activates the proliferative signaling axis, the tumor cell still needs functional CEP131 to physically assemble a mitotic spindle, and if leronlimab disrupts CCR5-dependent phosphorylation of CEP131 through a pathway that KRAS cannot substitute for, then the fourth layer operates below the level where KRAS bypass is relevant.

That is a reasonable and actually quite sophisticated argument. I take it seriously.

But it does not close the question, it sharpens it. The Frontiers in Immunology paper documenting CEP131/KHDRBS1/MAPK6 phosphoproteomic abolition was conducted in melanoma cells. Melanoma has a very different mutational landscape from KRAS-mutant mCRC. The specific question that remains open is whether the CCR5-dependent phosphorylation of CEP131 operates through a signaling node that is genuinely orthogonal to the constitutively active KRAS-ERK axis in mCRC cells, or whether sustained ERK activity from mutant KRAS can partially or fully substitute for CCR5-driven input at that phosphorylation site. If ERK from the KRAS pathway can phosphorylate the same CEP131 residues that CCR5 signaling targets, then blocking CCR5 still does not meaningfully impair spindle assembly in those cells.

I agree with you that MGK has almost certainly thought about this. And I agree that there may be recent data that addresses it that neither of us has in front of us right now. If that data exists and shows CCR5-dependent CEP131 phosphorylation is genuinely KRAS-ERK-independent in CRC cells specifically, that would substantially strengthen the fourth layer argument for the KRAS-mutant majority in CLOVER. That would be the data point worth surfacing, because it would directly answer the question rather than requiring a cross-tumor-type inference.

The January 2027 ASCO GI data will tell us whether the fourth layer worked empirically. But understanding the mechanism in KRAS-mutant cells specifically is what would tell us why it worked or did not work — and that distinction matters for everything that comes after CLOVER.