From the Bench, AACR D3 2026: Emerging Therapeutic Strategies to Inhibit KRAS, Enhance ADCs, and Tackle Resistance
More than 650 experts from academia, industry, venture capital, patient advocacy, and beyond attended the inaugural AACR Drug Discovery and Development (AACR D3) meeting, held in Boston from July 21 to 24, to hear about the latest developments in cancer treatment. (Check out this earlier blog post to learn about the insights shared by leading experts during the meeting’s opening panel session.)
Designed to showcase the continuum of drug discovery and development, AACR D3 2026 highlighted not only the therapeutics already showing promise in clinical trials, but also the many cutting-edge approaches that could shape the next generation of cancer treatments.
In this edition of “From the Bench,” we highlight some of these emerging therapeutic strategies, including ways to overcome resistance to KRAS inhibition, enhance antibody-drug conjugate (ADC) efficacy, and reverse lineage plasticity.
A One-two Punch: An EGFR-directed ADC With a KRAS Inhibitor Payload
The KRAS protein is mutated in about a quarter of all cancers, but until very recently, there were no drugs available that targeted this common cancer driver. Progress over the last decade has resulted in the approval of two small-molecule inhibitors of the KRAS G12C mutant. However, treatment resistance remains a challenge, and there are currently no approved inhibitors of other KRAS mutants.
Overcoming these challenges was a hot topic at AACR D3 2026, and among the many experimental therapeutics discussed was an ADC presented by Andrea Wang-Gillam, MD, PhD, co-chief executive officer, chief medical officer, and global head of research and development at Jacobio Pharmaceuticals.
An ADC is a type of targeted therapy that combines an antibody with a drug payload to selectively deliver the payload to cells expressing the target antigen that the antibody seeks. Currently approved ADCs deliver a DNA-damaging agent to cells, but the experimental ADC developed by Wang-Gillam and colleagues, JAB-BX600, is an EGFR-directed ADC that delivers an inhibitor of the KRAS G12D mutant protein.
Many KRAS inhibitors, including the one used in JAB-BX600, target the inactive form of KRAS. Cells can overcome these inhibitors by activating EGFR, an upstream regulator of KRAS, to generate active forms of KRAS that the inhibitor cannot target. By targeting both EGFR and KRAS G12D, JAB-BX600 aims to overcome resistance to KRAS inhibition that arises due to activation of EGFR.
Wang-Gillam reported that JAB-BX600 was effectively internalized into EGFR-expressing cells, killed tumor cells in vitro, and was 2,000-times more selective for tumor cells than normal skin cells. In animal models of colorectal and pancreatic cancers, which commonly harbor KRAS G12D mutants, a single dose of JAB-BX600 led to tumor regression, with minimal payload detected in plasma.
“Our EGFR-delivered KRAS G12D ADC is designed to maximize tumor-selective intracellular delivery while minimizing systemic payload exposure, potentially improving the therapeutic index,” said Wang-Gillam. “By integrating EGFR-mediated targeted delivery with suppression of adaptive EGFR-mediated feedback reactivation, our approach has the potential to achieve more durable MAPK pathway inhibition, delay resistance, and enhance antitumor efficacy.”
Two Targets, One ADC: A Dual-payload ADC Targets TOP1 and CDK7 in Breast Cancer
Conventional ADCs deliver a single payload, but new research suggests that doubling up on the payload to target two different cell signaling pathways may overcome resistance to trastuzumab deruxtecan (T-DXd, Enhertu), a single-payload ADC approved to treat certain breast cancers.
Kiyean Nam, PhD, chief executive officer and chief scientific officer of Qurient, presented preclinical results at AACR D3 2026 from an experimental dual-payload ADC called QP101 that targets cells expressing human epidermal growth factor receptor 2 (HER2) to deliver inhibitors of topoisomerase 1 (TOP1) and cyclin-dependent kinase 7 (CDK7).
TOP1 inhibition induces DNA damage, and CDK7 inhibition leads to transcription downregulation of DNA repair proteins, leaving cells unable to repair the damage. This may prevent cells from using DNA repair to overcome TOP1 inhibition, Nam said.
Compared to T-DXd—a HER2-directed ADC that delivers a TOP1 inhibitor—QP101 had greater antitumor activity in cells and xenograft models. QP101 was also effective in T-DXd-resistant models.
Nam explained that the mechanism of QP101 is intended to mimic what is seen in HER2-positive breast cancers with BRCA mutations, which tend to respond better to T-DXd than cancers with wild-type BRCA. Most HER2-positive breast cancers, however, have wild-type BRCA, he noted.
“By utilizing CDK7 inhibition to transcriptionally disrupt DNA damage repair pathways, QP101 induces pharmacological ‘BRCAness’ in wild-type cancer cells,” Nam said. “This alters the individual tumor biology, offering the potential for significantly increased clinical benefit in the broader HER2-positive patient population.
“QP101 represents a new strategy in drug development: Mechanistically customized ADCs designed specifically to address and overcome the biological limitations found in clinical setting.”
Insights Into T-DXd Activity: The Importance of Receptor State
Expanding the applicability of HER2-targeted ADCs may also depend on the status of HER2 itself, according to research presented at AACR D3 2026 by Sharanya Nag, PhD, a postdoctoral researcher at Memorial Sloan Kettering Cancer Center (MSKCC).
T-DXd is approved for breast cancers with varying levels of HER2 expression, including HER2-low tumors that would be considered HER2-negative, or nonamplified, by traditional diagnostic standards. Since HER2 amplification is not necessary for T-DXd activity, Nag and colleagues asked what other factors might determine efficacy of this ADC.
They analyzed real-world data from 272 patients with HER2-nonamplified (including HER2-low, HER2-ultralow, and HER2-null) metastatic breast cancer who had been treated with T-DXd at MSKCC. They found that 20 patients had tumors with activating mutations in ERBB2 (the gene that encodes HER2) and that patients with these tumor mutations had significantly longer progression-free survival than those whose tumors had wild-type ERBB2 (11 months vs. 6.2 months). Higher progression-free survival was also observed in the subset of patients with the lowest levels of HER2 expression (IHC 0: HER2-ultralow and HER2-null), who are currently not eligible for T-DXd.
In preclinical models, cells with ERBB2 activating mutations had greater accumulation of T-DXd than cells with wild-type ERBB2, despite having equivalent levels of HER2 protein on their cell surfaces. Further, a lower dose of T-DXd was needed to kill ERBB2-mutant cells compared with wild-type ERBB2 cells.
According to Nag and colleagues, these data raise the possibility that ERBB2 activating mutations increase turnover of HER2, thereby enhancing uptake of the bound ADC—a hypothesis that is consistent with prior work demonstrating the importance of HER2 internalization in T-DXd efficacy.
“Our work identifies activating ERBB2 mutations as a functional biomarker of trastuzumab deruxtecan sensitivity, demonstrating that receptor state—rather than HER2 expression alone—governs ADC efficacy through enhanced receptor internalization and payload delivery,” said Nag. “Importantly, our findings identify a genomically defined subset of HER2 IHC 0 patients, who are currently ineligible for T-DXd, that may benefit from this therapy.
“More broadly, they support biomarker-driven patient selection based on receptor biology and provide a framework for developing next-generation HER2-targeted ADC strategies.”
Tackling Prostate Cancer Resistance by Reversing Lineage Plasticity
Lineage plasticity, or the ability of cells to transition from one cell type to another, is an established mechanism by which cancer cells develop treatment resistance. In prostate cancer, the transition from a luminal epithelial state to a stem-like state is associated with attenuated androgen receptor (AR) signaling, and therefore, resistance to therapies that target AR signaling, leading to an aggressive disease.
So, could reprogramming cells to a luminal state resensitize prostate cancers to these therapies?
The answer may be yes, according to research presented at AACR D3 2026 by Giuseppina Carbone, MD, group leader of prostate cancer biology at the Institute of Oncology Research in Switzerland.
Prior research from Carbone and colleagues demonstrated that the transition of luminal prostate cancer cells to the stem-like state is driven by loss of the transcription factor ESE3/EHF (EHF). In the new study, Carbone and colleagues reasoned that increasing EHF levels may reverse the transition.
To test this hypothesis, they developed lipid polymer nanoparticles that encased and delivered EHF-encoding mRNA. They demonstrated that this delivery system led to increased EHF expression in various in vitro and in vivo models of prostate cancer, including cell lines, patient-derived organoids, patient-derived xenografts, syngeneic mouse allografts, and genetically engineered mice.
In cell line and murine models, EHF delivery reprogrammed cancer cells to a luminal epithelial state and restored their sensitivity to AR-targeted therapeutics, resulting in inhibition of tumor growth. In mice, systemic delivery of EHF-containing nanoparticles led to selective EHF expression in and inhibition of primary and metastatic tumors.
“Our findings address lineage plasticity, a major biological driver of tumor progression and therapeutic resistance in advanced cancers. There are currently no approved treatments designed to reverse this process,” said Carbone. “By restoring epithelial cell identity in tumor cells, our approach has the potential to resensitize tumors to standard therapies, enhance their efficacy, and improve patient outcomes. More broadly, this work establishes a proof of concept for a new class of reprogramming-based mRNA medicines that could be applied across multiple aggressive cancers driven by lineage plasticity.”
