Highlights from the EACR-Boehringer Ingelheim 2025 Conference: Drugging and Regulating the MAP Kinase Pathway

After a successful first meeting in 2023, the joint EACR and Boehringer Ingelheim virtual conference returned this year on 11 – 12 February 2025 with a focus on both the basic and clinical aspects of regulating signalling through the Mitogen Activated Protein Kinase (MAPK) pathway and its role in cancer. It was praised by participants for its high quality scientific content and speakers as “a fantastic opportunity to learn more what is happening in the world of MAPK pathway research and thinking about how it can relate to our own research”. Dr. Alexandra Boitor, EACR Scientific Officer, summarises here the main scientific takeaways from this meeting.

The MAPK pathway is one of the most commonly mutated signalling pathways in human cancers. While a range of small molecule inhibitors have been developed to inhibit the upstream and downstream effectors of this pathway, resistance remains a significant challenge. A thorough understanding of the mechanisms of intrinsic and adaptive resistance is crucial for the development of more effective agents.

In this spirit, the programme included new insights on the mechanism of action and resistance mechanisms to the new generation of pan-RAS inhibitors. The conference began with a keynote lecture from Dr Piro Lito from Memorial Sloan Kettering Cancer Center (USA). Dr Lito’s presentation started with a brief review of the most frequent KARS mutations in cancer, their effect on cancer progression and KRAS^G12Cinhibitors developed in the last decade, with a focus on Sotorasib, Adagrasib and Divarasib. Dr Lito’s presentation then focused on his group’s efforts to investigate in detail the mechanism of action through which KRAS^G12C inhibitors work [1] and how treatment resistance develops [2, 3]. The second part of the presentation discussed a new approach to targeting KRAS mutants, namely the use of active state selective tri-complex inhibitors [4, 5], and included early data from ongoing clinical trials for lung and pancreas cancer. The third part of Dr Lito’s talk focused on the ability of RAS mutants to hydrolyse GTP [6] and what this could mean for the treatment of KRAS-driven cancers.

The topic of tri-complex inhibitors that enable selective targeting of the active state of RAS proteins was discussed in a bit more detail later in the conference by Dr Mallika Singh from Revolution Medicines (USA). Starting with an explanation of the structural and molecular aspects of this new class of inhibitors [5, 7], Dr Singh continued by presenting data on the anti-tumour activity shown by a selection of these drugs in preclinical models of lung, pancreatic and colon cancer. Of note, this class of drugs seems effective against a range of KRAS G12 mutations [7]. Dr Singh also shared the latest data they have from clinical trials using one such pan-Ras inhibitor, Daraxonrasib, in patients with pancreatic cancer. To conclude her presentation, Dr Singh briefly touched on complementary design of active Ras inhibitors for monotherapy and combination strategies that raise the hope for a chemotherapy-free approach for the treatment of Ras addictive cancers.

Dr Miriam Molina Arcas from the Francis Crick Institute (UK) focused on an alternative approach to fight therapy resistance against KRAS inhibitors. Dr Molina shows in her research that KRAS^G12C inhibition increases inflammation in lung cancer, providing a rationale for combining KRAS inhibitors with immune checkpoint inhibitors [8]. Further on, Dr Molina went on showing that KRAS^G12C inhibition synergises with anti-PD1 therapy in hot tumour models but not in cold tumour models. Hence, her research focused on enhancing response in non-inflamed tumours by inhibiting SHP2 expression in addition to targeting active RAS^G12C and PD-1 [9].

Other interesting topics discussed during the conference included ‘Oncogenic KRAS mediated regulation of the pancreatic cancer microenvironment’ as explained by Dr Marina Pasca di Magliano from University of Michigan Medicine School, (USA); the potential of concurrent SOS1 and MEK suppression to inhibit signaling and growth in NF1-null melanoma as presented by Dr Sandra Misale from John Hopkins University (USA) and ‘Adaptive cancer mutability in response to targeted therapies’ exemplified through the research of Dr Alberto Bardelli from University of Torino (Italy). In addition, Marco Hofmann from Boehringer Ingelheim (Austria) provided a thorough review of the inhibitors developed against the RAS Signaling Pathway and the associated mechanisms of resistance with a focus on Boehringer Ingelheim’s contributions to this research field.

The scientific talks at this conference concluded with a keynote lecture from Dr Colin Lindsay from Manchester Cancer Research Centre (UK), who accentuated the need of a feedback loop between research and clinical practice to leverage KRAS precision medicine for optimum clinical benefit. In the first part of his presentation, Dr Lindsay articulated the current clinical challenges with Ras from therapy resistance and RAS inhibitor monotherapy toxicity to immune checkpoint blockade combination and non-G12C targeting. However, there is a raft of promising drugs targeting the MAPK pathway now available, so the second part of the presentation concentrated on identifying the translational ‘sweet point’ and the potential use of already collected patient samples in informing model generation and experimental settings to align preclinical and clinical research. The final part of Dr Lindsay’s presentation focused on his most recent research investigating the oncogenic properties and vulnerabilities of KRAS codon 13 mutations in non-small cell lung cancer [10, 11].

The research presented in the talks from the main programme was complemented by two poster sessions that broadened the discussion, focusing on various aspects of MAPK signalling. The conference draw to a close with a panel discussion, ‘New challenges for old therapeutic targets: What’s next?’, where the Scientific Programme Committee formed by Dr René Bernards from The Netherlands Cancer Institute (NL), Dr Anna Obenauf from Research Institute of Molecular Pathology (AT), Dr Chiara Ambrogio from University of Torino (IT) and Dr Marco Hofmann from Boehringer Ingelheim (AT) presented their views on the future of this research field and answered questions from the participants.

EACR Conferences

At the EACR we are dedicated to providing excellent cancer research conferences where the latest research topics and interaction for participants are the very highest priorities. Make sure you add the dates of the upcoming EACR Conferences to your diary now. Don’t forget we offer member discounts on all of our registration fees!

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References

1. Li, C., et al., The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS.Science, 2021. 374(6564): p. 197-201.
2. Xue, J.Y., et al., Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition.Nature, 2020. 577(7790): p. 421-425.
3. Awad Mark, M., et al., Acquired Resistance to KRASG12C Inhibition in Cancer. New England Journal of Medicine, 2021. 384(25): p. 2382-2393.
4. Schulze, C.J., et al., Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science, 2023. 381(6659): p. 794-799.
5. Holderfield, M., et al., Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.Nature, 2024. 629(8013): p. 919-926.
6. Cuevas-Navarro, A., et al., Pharmacological restoration of GTP hydrolysis by mutant RAS. Nature, 2025. 637(8044): p. 224-229.
7. Jiang, J., et al., Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discovery, 2024. 14(6): p. 994-1017.
8. Mugarza, E., et al., Therapeutic KRAS(G12C) inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv, 2022. 8(29): p. eabm8780.
9. Anastasiou, P., et al., Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade. Nature Communications, 2024. 15(1): p. 8146.
10. McDaid, W.J., et al., The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer. Molecular Cancer, 2024. 23(1): p. 253.
11. Adderley, H., et al., 113 (PB101): Targeting KRAS codon 13 mutations using direct combination approaches in non-small cell lung cancer. European Journal of Cancer, 2024. 211.