A New Challenge in Pancreatic Cancer Therapy ― The Promise of “Two Shots on Goal”

Introduction: Why Pancreatic Cancer Is So Difficult to Treat

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5-year survival rate of about 10%. Three major challenges underlie this poor prognosis:

1. KRAS-driven biology
   Nearly all PDAC cases harbor KRAS mutations that drive tumor initiation and progression.
2. Therapy resistance
   Even with newly developed KRAS inhibitors, responses are transient. Resistance and relapse inevitably emerge.
3. Failure of immunotherapy
   PDAC is an “immunologically cold” tumor. Unlike melanoma or lung cancer, checkpoint blockade has little to no clinical impact.

Thus, new strategies are urgently needed. One promising approach is the synergistic combination of KRAS inhibition with immune activation — aptly described as “Two Shots on Goal.”

---

First Shot: Forcing Persister Cells into Senescence and Harnessing CD4 T cells

(Broderick et al., Memorial Sloan Kettering/RevMed)

KRAS inhibitors induce strong tumor regressions, yet “persister cells” remain and seed relapse.

By combining a RAS(ON) multi-selective inhibitor (RMC-7977) with the CDK4/6 inhibitor palbociclib, researchers achieved:

• Conversion of persister cells into a senescence-like state.
• Secretion of a senescence-associated secretory phenotype (SASP) that recruits immune cells.
• Addition of a CD40 agonist leading to a CD4 T cell–dependent tumor–immune equilibrium.

Key finding: In mouse PDAC models otherwise prone to relapse, this triple therapy yielded durable regressions and extended survival.
This demonstrates a novel therapeutic concept: not just killing tumor cells, but locking survivors into senescence and letting the immune system finish the job.

---

Second Shot: Awakening the Immune System via KRAS Inhibition

(Orlen et al., University of Pennsylvania/RevMed)

This study asked: how does KRAS inhibition reshape the tumor immune microenvironment?

Key findings

1. T cell–poor tumors
   Tumors shrink but fail to achieve complete response (CR).
2. T cell–rich tumors
   Remarkably, 90% achieved CR after KRAS inhibition.
3. Tumor microenvironment remodeling
   • Reduction of suppressive MDSCs
   • Shift toward M1 macrophages
   • Infiltration and memory formation of CD8+ T cells
   • Increased MHC-I expression on tumor cells, making them more visible to immune attack
4. Combination with immunotherapy
   Deep and durable regressions, including complete responses not seen with either therapy alone.

Significance: KRAS inhibition is not just cytotoxic but also serves as an immune-sensitizing agent that can unlock the full potential of immunotherapy.

---

Commentary Perspective (Opsahl & Pasca di Magliano)

The accompanying commentary emphasized:

• KRAS inhibition alone is insufficient; durable remission requires a second shot — immune activation.
• Broderick’s senescence-driven CD4 T cell control and Orlen’s T cell–dependent regression reach the same conclusion via different routes.
• Together, they embody “Two Shots on Goal,” a potential paradigm shift in PDAC therapy.

---

Conclusion: The Road Ahead for Two Shots on Goal

These studies highlight a new horizon for PDAC therapy:

1. KRAS inhibition exerts dual effects — direct tumor killing and immune remodeling.
2. Immunotherapy gains new efficacy when paired with KRAS inhibition.
3. Combining senescence induction with immune engagement, alongside T cell–dependent regressions, points toward long-term remission and possibly functional cures.

If validated in clinical trials, this strategy could rewrite the history of pancreatic cancer therapy. Future directions include refining KRAS inhibitors, optimizing immune co-therapies, and identifying patients most likely to benefit.

---

References

1. Cancer Discovery, Vol.15, No.8 (2025).
   “Two Shots on Goal: Combination of RAS Inhibition and Immunotherapy Drives Long-term Remission in Pancreatic Cancer”
   Emily L. Lasse Opsahl
2. Cancer Discovery, Vol.15, No.8 (2025).
   “A RAS(ON) Multi-Selective Inhibitor Combination Therapy Triggers Long-term Tumor Control through Senescence-Associated Tumor-Immune Equilibrium in Pancreatic Ductal Adenocarcinoma”
   Caroline Broderick
3. Cancer Discovery, Vol.15, No.8 (2025).
   “T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma”
   Margo Orlen

---

This article was edited by the Morningglorysciences team.