April 17–22, 2026 · San Diego · 2418 items
← Medicinal chemistry beyond KRAS: CDK2, WEE1, SERD
6 people · 6 posts · 1 abstract
The 28-patient olaparib + T-DXd set is shared with the ADC chapter.
| Drug / trial | Readout | Setting |
|---|---|---|
| olaparib + T-DXdolaparib | Confirmed PR 42.9%, mDOR 11.2 mo | Same 28-patient set as the ADC direction |
Molecules that already cross ADC or breast (olaparib, CDK2) will be read again there.
Elizabeth K. Lee, Andrea Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Yinglu Zhou, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos
Read the abstract →Inhibiting ribosome biogenesis with BMH-21 resensitizes PARPi-resistant triple-negative breast cancer to olaparib. The drug combination was synergistic in 4 PARPi-resistant cell lines and in 3 BRCA wild-type TNBC cell lines with intrinsic PARPi resistance, but not in parental cells. In MDAMB231 cells, the combination increased γH2AX-positive cells up to 7.3-fold, SA-β-gal staining 5.6-fold and p21 3.6-fold, findings mirrored with CX-5461. Patient cohort data linked ribosomal pathway activity to MYC, proliferation, DNA damage and senescence.
RP-3467, a selective small-molecule inhibitor of DNA polymerase theta, suppresses Polθ enzymatic activity, abrogates microhomology-mediated end joining, and induces synthetic lethality in homologous recombination-deficient models. Combined with PARP inhibitors olaparib or rucaparib, it produced sustained tumor regression across multiple xenograft and patient-derived xenograft models without added systemic toxicity. In a phase 1 trial (NCT06560632), a heavily pretreated germline BRCA1-mutant ovarian cancer patient with a TP53BP1 loss-of-function mutation achieved a confirmed partial response to RP-3467 plus olaparib by RECIST v1.1.
Why it matters: First clinical response to a Polθ inhibitor in a PARPi-resistant HRD ovarian cancer patient with mechanistic preclinical support.
#AACR26 | ADC + #PARPi - finally a rational approach