Jasmin Hundal, Chair of Hematology-Oncology Research Fellowship Working Group at Cleveland Clinic, shared on LinkedIn:
“Resistance in HR+ breast cancer may be less about a pathway simply escaping therapy and more about how treatment itself reshapes tumor biology.
A recent Nature paper provides a mechanistic example.
CDK4/6 inhibition activates Rb to suppress the cell cycle.
But this study shows that activated Rb can simultaneously enhance ER-driven transcription, including pro-proliferative programs such as CCND1.
In endocrine-sensitive disease, endocrine therapy can counter this response.
In ESR1-mutant models, however, ER signaling persisted despite estrogen deprivation, while ER degradation restored deeper cell-cycle suppression.
This is particularly relevant as we move toward detecting ESR1 mutations before radiographic progression.
The implication is broader than ESR1: precision oncology increasingly requires us to understand not only the target, but how treatment changes the biology around that target.
Choosing the right drug may not be enough. Sequence and timing may be just as important.
As molecular monitoring moves earlier in the disease course, how should we determine when an emerging resistance mechanism is actionable rather than simply detectable?”
Title: Rb-driven transcription limits its tumour-suppressive effects in breast cancer
Authors: April C. Watt, Antonio Ahn, Catherine Blyth, Julia R. Dixon-Douglas, Krutika Ambani, Rhiannon Coulson, Michael Taylor, Keefe T. Chan, Catherine Dietrich, Brendan E. Russ, Susanne Ramm, Christabella A. Mahendra, Kun-Hui Lu, Nichelle Pires, Jesus Garcia-Sannicolas, Olivia Voulgaris, Sheena Nunag, Ching-Seng Ang, Mark A. Dawson, Elgene Lim, Monica Arnedos, Sarat Chandarlapaty, Fabrice André, Shom Goel
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