Slim Mzoughi, Assistant Professor at Icahn School of Medicine at Mount Sinai, shared a post on LinkedIn:
“Chemotherapy is still the frontline treatment for metastatic colorectal cancer — but why does relapse remain inevitable?
We have the answer, and the solution.
Recent work from the Batlle and Sansom labs show that CRC tumors can escape KRAS inhibition through cellular plasticity, rewiring from a MAPK-driven to a WNT/LGR5⁺-dependent state. These findings highlight the challenge: KRAS inhibition alone is not sufficient.
So, what do we do?
Almost a year ago now, we provided a mechanistically informed solution. We’ve shown that CRC tumors are heterogeneous, and cancer stem cells come in various flavors defined by two transcriptional programs: the canonical WNT-driven LGR5⁺ program and the non-canonical MAPK-driven Oncofetal (OnF) program. Importantly, OnF cells are inherently tolerant to chemotherapy, contributing to primary resistance, while LGR5⁺ cells can acquire adaptive tolerance by activating the OnF program.
Therapeutic implication/Solution: We demonstrated that combining standard chemotherapy (e.g., FOLFIRI) with KRAS/MAPK inhibitors, ideally including YAP inhibition, simultaneously targets LGR5⁺ cells and the OnF program. This strategy produces durable, experimentally validated responses and represents a rational path to improve clinical outcomes in CRC – we believe it is our best bet to achieve better outcomes in the clinic.”
More posts about Colorectal cancer.