← Return to New biomarker Claudin 18.2


New biomarker Claudin 18.2

Pancreatic Cancer | Last Active: Mar 29 1:40pm | Replies (13)

Comment receiving replies

KRAS, CHEK2 and ATM are entirely different pathways. The RAS/KRAS pathway of cell signaling is involved with cell growth and proliferation. CHEK2 and ATM serve different functions regarding DNA.

PARP inhibitors such as Olaparib, Rucaparib and Niraparib are being looked at in ATM and CHEK2 mutations.

KRAS G12D has a number of targeted therapies in clinical trials presently including MRTX1133, HRS-4642, and RMC-9805. Eli Lilly has a vaccine targeting KRAS in a phase II trial called ELI-002. The AMPIFY-201 trial is also looking promising.

Just above the G12 variations in the cell signaling path for RAS/KRAS/RAF/MEK/ERK is the RAS gene which serves as a master ON/OFF switch for cell growth and proliferation. The mutation causing uncontrolled growth causes the switch to be stuck in the “ON” position. There are a couple of trials for drugs considered a “pan” KRAS targeting small molecule drug designed to turn the RAS Master switch to OFF. RMC6236 and RSC-1255 are two trials underway.

Jump to this post

Replies to "KRAS, CHEK2 and ATM are entirely different pathways. The RAS/KRAS pathway of cell signaling is involved..."

^Indeed on the PARP inhibitors (PARPIs).^

My Guardant test, which reported both ATM Q268 and a CHEK2 splice site SNV, gives a list of clinical trials and drugs relevant to each mutation.

For ATM and CHEK2, it gave the same drug result: Olaparib or Talazoperib, both of which are PARPIs.

But those are only trials. There have been positive results and approvals for PARPIs on patients with BRCA1/2 and PALB mutations. Although ATM is similar in its impact on DDR (DNA Damage Response/Repair), early PARPI results have not been as promising on ATM. My oncologist is not even convinced the study conclusions were statistically significant for the BRCA/PALB patient population, but it's obviously working well for some patients in that group.

So... there might be a PARPi in my future, or a different oncologist, or both, or neither. One study I read (lost the link) suggested that by the time a cancer becomes resistant to platinum drugs, it is also resistant to PARPIs, so it might be getting too late for me to go that route.

My very limited understanding of cancer biology is that traditional, cytotoxic chemotherapy (Standard of Care) drugs mainly just attempt to "poison" fast-growing cells to death (explaining side effects like hair loss). In more detail, that may involve "breaking" some function they need in order to reproduce successfully.

By comparison, the more targeted genetic therapies can attack from two angles: 1) Turning on a switch that will help your immune system kill or suppress cancer cells; and 2) Turning off a switch that causes cancer cells to grow out of control.

The RAS-based therapies seem to be a promising version of #2 above, fighting cancer offensively and proactively on the front lines, rather than #1 which is more like fighting defensively and reactively inside your own territory. That's my non-medically trained analogy and visualization of it anyway... I hope it's correct, accurate, and helpful.

Do you know if they test these clinicals or vaccines on the murine population with success, first?

Thank you for your thorough response!