science

TARGETING CANCER’S MOST commonly mutated pathway

Why RAS/MAPK?

There are approximately 5.5 million new cases of cancer per year with RAS/MAPK pathway alterations, over 90% of which have limited or no treatment options. While the RAS/MAPK pathway has been well characterized and validated based on the development and approval of multiple compounds targeting discrete signaling nodes in the pathway, most of these compounds face resistance and tolerability challenges, highlighting the need for new approaches to target this important signaling cascade.

Implicated in approximately one-third of solid tumors, including:

Glioblastoma multiforme (GBM)
Head & neck squamous cell carcinoma (HNSCC)
Non-small cell lung cancer (NSCLC)
Colorectal cancer (CRC)
Melanoma
Pancreatic ductal adenocarcinoma (PDAC)

Implicated in liquid tumors,
including:

Acute myelogenous leukemia (AML)

Our mission will involve delivering new therapies to patients in markets where there are limited or no approved therapies, which are referred to as “blue oceans” (Blue Ocean Strategy by Chan Kim & Renée Mauborgne), as well as markets where there are already approved product offerings, or “red oceans.” Of the approximately 5.5 million new patients diagnosed globally per year with cancers driven by RAS/MAPK pathway alterations, over 70% (approximately 4 million patients) are in blue oceans with limited or no treatment options.

New cases estimated
worldwide per annum (thousands; numbers may not
add up due to rounding)

Alterations	GBM	HNSCC	NSCLC	CRC	Melanoma	PDAC	Other solid tumors	AML	US	EU	ROW	Global
EGFR*/FLT3	125	513	184	338	–	–	–	61	82	222	917	1,220
NF1	25	58	98	34	33	1.9	434	3.2	75	159	453	687
KRAS G12C	–	2.8	240	57	–	5.1	45	0.1	36	82	232	350
KRAS G12D	0.2	4.7	68	238	0.5	178	201	1.3	65	171	456	692
RAS Q61X	0.4	23	35	80	69	32	155	4.1	51	106	242	399
RAS G13R	–	9.4	5.9	5.5	2.1	–	14	0.5	3.6	8.1	26	37
Other RAS	0.6	31	162	452	4.4	211	331	13	112	291	800	1,203
BRAF V600E/K	2.0	1.9	23	180	93	1.4	158	0.4	63	127	271	461
BRAF Class 2	0.4	3.8	18	6.9	5.3	0.5	57	–	11	23	58	92
BRAF Class 3	0.1	0.9	12	17	2.5	–	29	0.2	6.1	15	40	61
Other BRAF	–	–	3.9	–	1.9	0.3	0.5	–	0.7	1.0	4.9	6.6
MEK	0.2	1.9	12	8.8	4.6	0.2	22	–	5.2	11	33	50
Co-occurring activating MAPK pathway alterations**	1.4	10	62	59	37	7.1	84	3.0	33	69	162	264
US	12	29	93	114	77	51	153	11	542
EU	34	76	194	398	116	124	324	18		1,285
Rest of World	109	555	635	964	60	264	1,053	57			3,696
Global	155	660	923	1,476	253	438	1,530	86				5,522
	Blue ocean opportunties					Red ocean opportunties
* Post-Osimertinib resistant population shown for EGFRm NSCLC except for SCLC transformation ** Co-occurring activating MAPK pathway alterations exclude EGFR overexpression Source: SEER database (2020), ECIS database (2020), GLOBOCAN database (2020), The AACR Project GENIE Consortium version 8.1 (2020), TCGA Research Network: https://www.cancer.gov/tcga, Tyner JW et al. (2018) PMID: 30333627, Brenner CW et al (2013) PMID: 24120142, Chen J et al. (2020) PMID: 32015526, and Ostrom QT, et al. (2020) PMID: 33123732

MAPKlamp & More

Using innovative science and working with world-class collaborators, we are taking a holistic, modality-agnostic approach to effectively shut down the RAS/MAPK pathway. We are not just targeting individual signaling nodes. Rather, we seek to turn off multiple nodes and cooperative mechanisms along the pathway in parallel. To accomplish this, we are pursuing three therapeutic strategies that work together to comprehensively, and perhaps synergistically, shut down the RAS/MAPK pathway.

Our 3 therapeutic strategies

To learn more about our three therapeutic strategies and how they can help us overcome RAS/MAPK pathway-driven cancers, click on the numbers below.

Target upstream and downstream MAPK nodes

with single agents and
clamp oncogenic drivers (MAPKlamp^™) with combinations

Our proprietary MAPKlamp strategy targets upstream and downstream nodes of the RAS/MAPK pathway, initially SHP2 (ERAS-601) and ERK (ERAS-007), respectively, to shut down, or clamp, the signaling of various oncogenic drivers, such as RAS, RAF, and MEK alterations, trapped in between these nodes. With our MAPKlamp approach, we hope to induce tumor regression in RAS/MAPK pathway-driven cancers, while also blocking their main escape routes. We are also discovering and developing single agent and combination approaches to target other upstream nodes that impact the RAS/MAPK pathway such as EGFR (ERAS-801), a receptor tyrosine kinase that represents a key escape route for MAPK signaling, and SOS1 (ERAS-9), a guanine nucleotide exchange factor that enables RAS to cycle from the inactive GDP state to the active GTP state.

Target RAS directly

with single agents and combinations with
upstream, downstream,
and escape route targeted
therapies

Targeting RAS directly with single agents and combinations. We are discovering and developing molecules with the potential to inhibit RAS in its inactive GDP state as well as its more prevalent active GTP state. Utilizing our in-house discovery efforts employing structure-based drug design, we are developing a central nervous system (CNS)-penetrant inhibitor of KRAS G12C (ERAS-1), which is the only RAS isoform and mutation that is more commonly present in the inactive RAS-GDP state. We are also developing proprietary compounds against KRAS G12D (ERAS-4), which is more commonly found in the active RAS-GTP state and is the most prevalent KRAS mutation. Our approach to targeting other RAS isoforms and mutations also found more commonly in the RAS-GTP state is based on the foundational discoveries of one of our co-founders, Dr. Kevan Shokat, a world-renowned pioneer of novel therapeutic approaches targeting key cancer signaling pathways such as the RAS/MAPK pathway.

Target escape routes

enabled by other proteins
or pathways to further
disrupt RAS/MAPK
pathway signaling

Targeting escape routes enabled by other proteins or pathways to further disrupt RAS/MAPK pathway signaling. RAS-driven cancers utilize cooperative mechanisms to develop resistance. As an example, RAS-driven cancers can become dependent on autophagy, which becomes constitutively active and represents a potential escape route for metabolically active tumors such as pancreatic ductal adenocarcinoma. By targeting ULK (ERAS-5), a key regulator of autophagy, in combination with our RAS targeting agents, we aim to shut down this potential escape route for RAS-driven cancers. We also are actively pursuing various ways to further disrupt RAS/MAPK pathway signaling by degrading key proteins. Finally, MYC (ERAS-11) is a transcription factor and oncogene that is overexpressed in the majority of cancers and a key enabler of RAS/MAPK pathway signaling at the transcriptional level.

Our strategic focus on the RAS/MAPK pathway allows us to comprehensively target every critical node in the pathway that could drive signaling. In fact, we currently have programs targeting each of the nodes colored in purple below.

Presentations

Naporafenib (ERAS-254)

ERAS-007

ERAS-601

Publications

EGFR

SHP2

RAS-GDP

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Nature, November 2013
Jonathan M. Ostrem, Ulf Peters, Martin L. Sos, et al.