# Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2023 · $666,289

## Abstract

Project Summary
Although the development of targeted therapies has improved overall cancer patient survival, adaptive
responses by tumor cells can render these treatments ineffective. The development of agents that block adaptive
responses, thereby increasing treatment durability is desperately needed. We and others have demonstrated
that inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidates
to combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13
inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcome
therapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overall
objective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiring
and develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis is
that CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13
will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for this
project posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticity
as an adaptive stress resistance mechanism, and (ii) elucidation of mechanisms underpinning compound action
will offer a strong scientific framework that will facilitate future clinical development of these new agents for
improved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimize
the drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanisms
whereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3)
Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitor
resistance in NSCLC. Accordingly, using a battery of approaches, we will: a) optimize key CDK12/13 inhibitor
parameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translational
mechanisms, whereby SR-4835 provokes resensitization to chemotherapy, and c) validate cell-based
observations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovative,
as our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecular
probes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii)
evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting, more
durable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drive
drug resistance. The proposed research is highly significant and provides a strong scientific rationale for the
continued develo...

## Key facts

- **NIH application ID:** 10686136
- **Project number:** 5R01CA262530-03
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Derek Ronald Duckett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $666,289
- **Award type:** 5
- **Project period:** 2021-07-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686136

## Citation

> US National Institutes of Health, RePORTER application 10686136, Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers (5R01CA262530-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10686136. Licensed CC0.

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