PO.ET01.02 · 实验与分子治疗
Rezatapopt and KRAS inhibitors for the treatment of TP53 Y220C and KRAS mutant cancers
作者与单位
摘要 Abstract
Background: TP53 and KRAS are two important genes involved in cancer development. KRAS is involved in cell growth and division, and KRAS mutant cancers often do not respond to treatments. P53 is a transcription factor that regulates cell cycle and prevents tumor formation. Cancer cells with TP53 mutations can evade p53-mediated tumor suppression. Combined TP53 / KRAS mutations are associated with drug resistance and worse prognosis. Rezatapopt is a small molecule reactivator of p53 Y220C protein. It binds the mutant protein and stabilizes p53 structure in the wild-type conformation restoring its functions. TP53 Y220C is present in approximately 1% of all solid tumors. We hypothesized that rezatapopt in combination with standard or targeted therapies enhances treatment response in TP53 Y220C/ KRAS altered tumors.
Methods: We used three TP53 Y220C cell lines that also had KRAS G12D or Q61H mutations to analyze the effects of drug combinations. Following a high-throughput screening with 23 drugs using an ATP quantification-based cell viability assay, we selected 6 agents and confirmed the results using sulforhodamine B (SRB) assay. We used Chou-Talalay and Bliss methods to calculate IC50 and combination index. We analyzed the effect of rezatapopt in combination with pan-RAS inhibitors on long-term viability of treated cells by colony formation assay. In vivo antitumor activity was assessed by objective response and event-free survival (as defined by time to tumor doubling) per PDXNET metrics.
Results: Rezatapopt was synergistic with multiple chemotherapeutic and targeted therapy agents. SRB assay showed that both MRTX1133 (KRAS G12D inhibitor) or daraxonrasib (RMC-6236, pan-RAS inhibitor) were synergistic with rezatapopt in two TP53 Y220C and KRAS G12D cell lines. We generated a patient-derived xenograft model from a patient with colorectal cancer bearing TP53 Y220C and KRAS G12A mutations, and treated the model with rezatapopt (100 mg/kg, QD, PO), daraxonrasib (25 mg/kg, QD, PO), or the combination. Four out of 5 rezatapopt + daraxonrasib combination-treated tumors regressed greater than 30% from baseline by day 22 while only 1 out of 5 tumors treated with either single agent regressed by day 22. Event-free survival was significantly longer for combination-treated mice compared to mice treated with daraxonrasib alone (p=0.013) or rezatapopt alone (p=0.016).
Conclusion: Rezatapopt combined with KRAS inhibition increased antitumor activity. Further studies are needed to understand the mechanism of synergy.
利益披露 Disclosure
A. Akcakanat, None.
E. E. Dumbrava,
Bayer HealthCare Pharmaceuticals Inc, Immunocore LTD, Amgen, Aileron Therapeutics, Compugen Ltd, Gilead, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma ).
Triumvira Immunologics, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Rain Oncology, Astex Therapeutics, Sotio Biotech, Poseida ).
Mersana Therapeutics, Genentech, Boehringer Ingelheim, Dragonfly Therapeutics, A2A Pharma, Volastra ).
AstraZeneca, Modex Therapeutics, Fate Therapeutics, Pfizer, Jacobio ).
BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics, PMV Pharma, Fate Therapeutics, Astra Zeneca Other, Advisory Board.
PMV Pharma, Boehringer Ingelheim, BOLT Therapeutics Other, Speaker.
ASCO, AACR, LFSA Association, Rain Oncology, Banner MD Anderson Cancer Center, Triumvira Immunologics, KSMO, Boehringer Ingelheim Travel.
K. W. Evans, None..
R. Zhang, None..
M. Zhao, None..
A. Kennon, None..
X. Zheng, None..
S. M. Scott, None..
E. Yuca, None..
G. Raso, None..
E. K. Kong, None..
Y. Rizvi, None.
D. Hong,
280 Bio, AbbVie, Adaptimmune, Adlai-Nortye, Alterome, Amgen, Astelles, Astra-Zeneca, Bayer, BeiGene USA, BioBridge, Biomea Fusion ).
Bristol-Myers Squibb, Chong Kun Dang, Deciphera, Eli Lilly, Endeavor, Erasca, Exelixis Inc., F. Hoffmann-LaRoche, Genentech, Immunogenesis, Incyte Inc. ).
Inhibrix, Merck, Mirati, NCI-CTEP, Novartis, Pfizer, Quanta Therapeutics, Revolution Medicines, VM Oncology ).
American Association of Cancer Research (AACR), American Society of Clinical Oncology (ASCO), Bayer, BeiGene USA Inc., Genmab, Immunogenesis, Medscape, Mirati Therapeutics Inc., Pfizer Travel.
Society for the Immunotherapy of Cancer (SITC), Telperian Travel.
280 Bio, Acuta Capital Partners LLC, Alpha Insights, Amgen, Bayer, BluePrint Medicine, Boxer Capital, Children’s Oncology Group, COR2ed, Cowen Group Inc, Crossbridge Bio, Ecor1 Capital, Erasca Other, Consulting, Speaker, or Advisory Role.
Gerson Lehrman Group Inc., Group H, Guidepoint, Immunogenesis, Jansen Pharmaceuticals, Kestrel Therapeutics, Medacorp, Medscape, Orbi Capital, Pfizer Other, Consulting, Speaker, or Advisory Role.
Remedy Inc, Revolution Medicines, T-Knife, Travistock Group, WebMD, Yiling Pharmaceutical. Other, Consulting, Speaker, or Advisory Role.
Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder, Advisor), CrossBridge Bio (Advisor) Other Business Ownership.
M. V. Poyurovsky,
PMV Pharmaceuticals Inc. Other, Shareholder.
G. Lozano,
PMV Pharmaceuticals Inc. Other, Scientific Advisory Board.
A. Korkut,
BostonGene Other, Salary Support.
F. Meric-Bernstam,
AstraZeneca Pharmaceuticals, Becton Dickinson, Biocartis NV, Calibr a division of Scripps Research Institute, Daiichi Sankyo, Dava Oncology, Debiopharm, eFFECTOR Therapeutics, Elevation Oncology Other, Consulting.
Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LigaChem Biosciences, Lengo Therapeutics, Menarini Group, Molecular Templates, Protai Bio, Ribometrix, SystImmune Other, Consulting.
Tallac Therapeutics, Tempus, Vir Biotechnology, Zymeworks Other, Consulting.
Cybrexa, go Therapeutics, Guardant Health, Harbinger Health, Illumen Therapeutics, Kivu Biosciences, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Sanofi Pharmaceuticals, Seagen Other, Advisory Committee.
Theratechnologies and Zentalis Pharmaceuticals Other, Advisory Committee.
Aileron Therapeutics, AstraZeneca Pharmaceuticals, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis Inc., CytomX Therapeutics, Daiichi Sankyo, Debiopharm, eFFECTOR Therapeutics ).
Genentech, Guardant Health, Jazz Pharmaceuticals, Klus Pharma, Novartis, Puma Biotechnology, Taiho Pharmaceutical, Takeda Pharmaceutical, Zymeworks ).
Dava Oncology Other, Honoraria.
European Society for Medical Oncology (ESMO), European Organisation for Research and Treatment of Cancer (EORTC), Cholangiocarcinoma Foundation, Dava Oncology, Physician Education Resource Travel.